Reviewing Potential Strategies for the Rejuvenation of Stem Cell Populations

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Every type of tissue is supported by its own dedicated stem cell population, delivering a supply of daughter somatic cells that replace losses and maintain tissue function. Unfortunately, stem cell function declines with age. This has numerous causes, all of which descend from the underlying accumulation of molecular damage outlined in the SENS research proposals for rejuvenation biotechnologies. Downstream of those causes, stem cells become less active due to some combination of internal damage, damage to their niche of supporting cells, and changes in the signaling environment. The latter two classes of issue appear more influential in the best studied stem cell populations, such as the satellite cells of muscle tissue.

Thus most research and development intended to restore stem cell function is presently focused on trying to override signaling or cell programming in order to force stem cells into greater activity, regardless of the present state of their environment. This may produce benefits to tissue function that are sizable enough to be worth the effort and cost of development, but one cannot just forever ignore the underlying damage of aging with impunity.

For one thing, not every aspect of aging can be fixed by throwing cells at the problem: there are protein aggregates and other forms of molecular waste that are not adequately cleared for reasons that have little to do with stem cells. There is mitochondrial dysfunction throughout cell populations. And so forth. Further, is most likely that stem cells falter in function in response to a damaged environment because this acts to limit cancer risk, though at the cost of a drawn out decline. Thus many of the strategies outlined in this open access paper may turn out to have increased incidence of cancer as a side-effect, even when they achieve meaningful gains in the near term.

However, we can balance that expectation against the animal studies of telomerase gene therapies to lengthen telomeres. In mice that approach both improves stem cell function and reduces cancer risk. In that case, it may be that improved function of the immune system in anti-cancer immunosurveillance offsets the raised risk due to forcing damaged cells into greater activity. That said, a great deal more work is required to understand where the line is drawn on cancer risk in the many approaches to improved stem cell function.

Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging

DNA damage accumulation is critical for age-dependent loss of tissue-specific stem cell function. This type of accumulation is dependent on the attenuation of the DNA repair and response pathway. For example, DNA damage markers, such as histone H2A phosphorylation and comet tails, have been quantified in hematopoietic stem cells (HSCs) and muscle stem cells (MuSCs) from young and old mice and indicated strand breaks significantly accrue in HSCs and MuSCs during aging. It is therefore reasonable to suggest that an increase in the activity of DNA repair pathways may slow down or prevent the accumulation of age-related defects in stem cells and thereby promote the healthy function of aged tissues.

A gradual decline of the telomere length that occurs through the loss of telomerase during aging has been observed in mouse and human tissues. In the mouse model, the loss of telomerase displays telomere shortening, stem cell depletion, and impaired tissue injury responses. However, with telomerase reactivation, telomerase reverse transcriptase (TERT)-deficient mice extend telomeres and reverse degenerative phenotypes. Protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, is highly expressed in young HSCs, whereas it progressively declines with age. In aged mice, treatment with exogenous Pot1a protein could reverse the HSC activity and sustain their self-renewal.

Increased expression of several cell cycle inhibitors, such as p53/p21, p16Ink4α, p19Arf, and p57Kip2 can lead to an essentially irreversible arrest of cell division and promote stem cell senescence. In MuSCs, HSCs, and neural stem cells (NSCs), the expression of p16Ink4α accumulates with age, but p16Ink4α repression through various methods can improve the function of aged stem cells and prevent cellular senescence. For example, silencing of p16Ink4α expression in geriatric satellite cells restores their quiescence and regenerative potential. In a potentially insightful study, researchers showed that autophagy is critical to the prevention of stem cell senescence by repressing the expression of p16Ink4α, and treatment with pharmacological rapamycin to stimulate autophagy could rejuvenate the MuSCs.

Many studies point that altered epigenetic marks of aging stem cells not only alter the transcriptional programs that dictate the function of the stem cells but also alter the potential differentiation towards distinct effector lineages. Recently, aberrant global and site-specific induction of active chromatin marks such as Hoxa9, has been investigated in aged satellite cells, while the inhibition or deletion of Hoxa9 can improve MuSC function and muscle regeneration in aged mice. Another example of successful rejuvenation comes from a study in which aged HSCs express a lower level of the chromatin organizer Satb1 than their young counterparts, while overexpression of Satb1 can improve their ability to generate lymphoid progeny via epigenetic reprogramming.

Signals can directly influence all aspects of stem cell functions including quiescence, proliferation, and differentiation. Signaling pathways involving p38-MAPK, janus kinase (JAK) / signal transducers and activators of transcription (STAT), Notch, and mechanistic target of rapamycin kinase (mTOR) contribute to the modulation of tissue stem cell functions, and their changes with age could affect tissue maintenance and repair systems. Hence, the proper modulation of these pathways is related to the reverse senescence of adult stem cells, which present the enhanced regenerative capacity of the tissues. For example, following overactivation of the p38α/β MAPK pathway, aged satellite cells are over-activated, and then increasingly generate their committed progenitors, while reducing self-renewal. However, pharmacological inhibition of p38α/β MAPK in aged satellite cells is able to restore the engraftment potential and improve their self-renewal ability by restoring asymmetric division.

It is known that tissue-specific stem cells are located in niches. The niche components can be considered somatic and stromal cells, immune cells, extracellular matrix (ECM), innervating neuronal fibers, and the vasculature. Although the niche structure varies among the different adult stem cell types, the stem cell niche provides essential cues to influence cell fate decisions. The aging of niche cells and age-dependent alterations in the components of stem cell niche are able to cause a loss of stem cell function. Fibroblast growth factor-2 (FGF-2), for example, is upregulated in the aged satellite cell microenvironment, whereas inhibition of FGF signaling can rescue the self-renewal capacity of old MuSCs. In addition, the cell surface receptor β1-integrin and the ECM protein fibronectin are dysregulated in aged MuSCs, and reconstitution of these components is able to restore the muscle regenerative capacity.

In addition to stem cell niche, aging also causes changes in circulating signals that directly or indirectly impact functions of tissue stem cells. These signals include soluble molecules secreted by any tissue in the body, which can be hormones, growth factors, and other signaling molecules or immune-derived signals secreted by infiltrating immune cells. Wnt ligand level is higher in old mouse serum and canonical Wnt signaling directly antagonizes Notch signaling in satellite cells. But Wnt inhibitors effectively restored the satellite cell function in aging, and a similar result is obtained in aged mesenchymal stem cells. The level of TGF-β is significantly increased in old human and mouse serum, which causes the damage and senescence of satellite cells. However, blockage of TGF-β signaling can reverse the activity of satellite stem cells, improving the myogenesis of aged mice.

Senescent cells accumulate with aging in several tissues of humans and animals, which is a common feature of age-related pathologies. Not only differentiated cells but also tissue-specific stem cells become senescence during aging. Moreover, the complex senescence-associated secretory phenotype (SASP) is highly expressed with accumulated senescent cells, which can alter the microenvironment and contribute to age-related pathologies. For example, the tissue regenerative capacity is impaired by the limited stem cell function because of their senescent state. And this decreased regenerative capacity is also regulated by the SASP that is secreted by senescent cells. Thus, the selective clearance of senescent cells and SASP suppression will be a promising therapy for age-related diseases. This concept has been successfully tested in physiologically aged mouse models.

As stem cells are the longest-living cells within an organism, stem cell aging is highly relevant as a driver of organismal aging, health, and longevity. In this review, we demonstrate that by targeting aging mechanisms, the aging associated phenotypes and functions of tissue-specific stem cells can be reversed. These restorative interventions hold promise for the possibilities of regenerative medicine and the treatment of many age-related diseases and dysfunctions.

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Jim Mellon Interviewed by Adam Ford at Undoing Aging 2019

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Adam Ford of Science, Technology, and the Future carried out a number of interviews while at Undoing Aging in Berlin earlier this year. The interview materials are steadily being processed and uploaded, and that just recently included this interview with Jim Mellon, billionaire investor and philanthropist, cofounder of Juvenescence, and a very down to earth fellow who is interested in improving the human condition by targeting aging with new biotechnologies. Accordingly, he has used his resources to put himself into a position to talk up the longevity industry, move research forward, and attract a great deal more funding for the next stage in the process of guiding the first treatments to slow and reverse aspects of aging from the laboratory to the clinic. These are interesting times, as our community expands considerably, and the state of the science and the medicine is progressing ever more rapidly.

My name is Jim Mellon, and I’m the chairman of Juvenescence, which is a company involved in the science of longevity. It is relatively recently formed, it is about a year and a bit old, but we’ve raised a significant amount of funding – nearly $160 million now – in the last year to advance the cause of longevity science. By the end of this year, we will have made 18 investments. Most of them are subsidiary companies of ours, so we control those companies. We give both development and financial backing to the scientist-entrepreneurs and institutions that we collaborate with.

I am fortunate to have two partners who have broad experience in the biotech and healthcare area, in particular Declan Doogan, who was the head of drug development at Pfizer for a long period, and then he worked at Amarin, which as you know is a very successful biotech company with a nearly $10 billion market valuation today. About four years ago, the three of us started a company called Biohaven, which is now listed on the New York Stock Exchange and has a valuation of about $2.5 billion. The company has approval for a drug for migraine, which will be on the market in the US next year. There is a good team of veteran drug developers who have come together to create this Juvenescence company, and we’re very, very excited about it. We’re the biggest investors in the company ourselves, on the same terms as other investors. We will take the company public in the first quarter of next year, barring market disasters, and probably on the US stock exchanges.

We’re interested in this field of longevity science and able to raise significant funding because we’ve been in biotech for quite a long period of time, together, and created a number of companies. It seemed to be a natural outgrowth of the great developments that have occurred in the last few years. The unveiling of the human genome identified aging pathways that can now be manipulated. For the first time ever, you and I are in the cohort that is able to be bioengineered to live a healthier and longer life. It is still in a very primitive stage; we’re in the internet dial-up era equivalent, but the science is advancing very quickly.

I always say that I wrote my first book on biotech seven years ago, it was called Cracking the Code, and since then we’ve had CRISPR/Cas9, which didn’t exist seven years ago, we’ve had the cure for Hepatitis C, we’ve had artificial intelligence for the development of novel compounds. The latter of which is a key part of our strategy, as investors in In Silico Medicine, which I think you are familiar with. Then, of course, you have cancer immunotherapy, which didn’t exist seven years ago, and is now a $100 billion / year industry. So what is going to happen in the next seven years? We don’t know, but you can bet that it is going to be very, very good. So, if you want to regard it as a casino table, we’re covering all the markers that we can with the funds that we’ve raised. We hope to raise a substantial further amount on the initial public offering of the company in the first quarter of next year, and that will give us enough resources to carry out five phase II trials without partners, so that we can get the maximum leverage on the products that we’re developing.

So far we’ve invested in small molecules, which is the specialization of our team. For instance we have a senolytic drug in development in that area. We’ve also invested in stem cells; we’re the largest investor in Mike West’s company AgeX Therapeutics, which is now a public company in the US. We own about 46% of that company. Then via Lygenesis we’ve also got our first product going into patients in the first quarter of next year, sick patients in a phase II trial, for organ regeneration, regenerating the liver, using hepatocytes to seed lymph nodes to act as organic bioreactors to grow fully functioning liver tissue. The FDA has agreed to the protocol for doing that in sick patients, which is a remarkably fast path to demonstrating successful outcomes in that area. If that is successful, then we will look to regenerate other organs, in particular the thymus, which as you know is related to aging in a big way.

So we’re moving very, very quickly. We’ve got great colleagues; Margaret Jackson from Pfizer is on our team. Howard Federoff, ex-Pfizer, is on our team. Annalisa Jenkins, who was head of drug development and research and development at Merck Serono, a very big company, is on our team. We’ve put it all together remarkably quickly. But we have experience in doing that, and so we’re full of confidence. This is a remarkable time to be alive, and I want to be alive for at least another 20 or 30 years beyond what would be considered to be my allotted life span. The same is the motivating factor for my cofounders, Declan Doogan and Greg Bailey.

Working to extend life is an ethical cause. No-one can argue, successfully at least, that this isn’t a good thing to do. There are some people who say “well, it is for the haves and not for the have-nots” but that is rubbish, because ultimately all these drugs will become generally available, and some of them already are. Metformin, which as you aware is a drug that has some anti-aging properties, costs essentially nothing. It is a generic drug. In the same as antibiotics and ulcer drugs and so forth were once expensive and are now very cheap, the same thing will happen to drugs for longevity. Gene therapy and stem cells is another matter, though, and that will probably be an expensive thing for some time to come. But undoubtedly, the cost will come down for those as well.

The other people who argue against work on aging talk about overpopulation; if there are all these old people, will there be enough room on the planet. Well the answer is, we’re already alive, so we’re not going to be adding to the population. You and I are already here. The big issue on population is how many children does each woman have around the world, and that figure is falling dramatically, to the point where we can see populations actually shrinking. Just as an example, if Japan doesn’t all immigration, or doesn’t have a baby boom, its population will fall from 126 million today to 50 million by the year 2100. So both those arguments, the haves versus the have-nots, and the overpopulation concern, are nonsensical arguments. In my view there is absolutely no reason why governments, institutions, the general population, the voting population, shouldn’t be pushing really hard to make this happen.

Regarding the aging of the existing population and how to cope with it, the main point made by Aubrey de Grey, and other eminent scientists as well, is that if you treat the top of the cascade of damage in aging, then you are going to treat the underlying diseases of aging that pharmaceutical companies are trying to address. But for those pharmaceutical companies, it is a whack-a-mole exercise, so if you get one disease and that is cured, then you’ll get another one, and they’ll have to cure that one. Ultimately we become destabilized and we die, all of us. So let us try and treat aging as the central disease, and from that as the unitary disease, we’ll be treating the cascade that follows from that.

Some people say it is hubris to target aging, but I think that this is because until relatively recently nothing worked. It has been an aspiration of human beings for millennia to find the fountain of youth, and nothing has worked. So people are skeptical about the fact that it might be working now. Why now rather than 20 years ago or 20 years in the future? But the fact is that it is now, and we need to seize the moment and rise to the challenge. We need much more funding to come into this area, and that funding will drive the science. We need many more advocates for this cause to come to the fore and spread the word, that this is going to be monumentally great for humanity.

In my own case, I’ve set up a charity with Andrew Scott, who wrote The 100 Year Life, and we do a Longevity Week in London. We did the first one last year, and we’re doing the next one in November of this year, to spread the word. This will have a big societal impact, on consumption, on the way in which we look at the trajectory of life, but it is also going to have a major impact on us as human beings. In the past you’d have expected to live to about 85 or 90, the same with me, and now we’re very likely to live to 110 or 120. So let’s do it. Let’s make it happen. I think that all of us, yourself, myself, have relatives, dear friends, acquaintances, who are suffering the indignities of aging as it currently exists. We would like to relieve that burden of suffering by extending the healthy span of life. The personal motivation is a very big factor. Here in Berlin, there are 300 or 400 people at this conference, and I imagine that all of them, beyond the business side of things, have an altruistic motivation for this as well. More people need to do it, so get on to it!

The elevator pitch for high net worth people thinking about investing in this space is that, first of all, we’re at the front end of a huge upward curve. I said earlier on that this was like the internet dial up phase of longevity biotech. If you’d invested in the internet in the very early days, you’d be more than a billionaire now, you’d be one of the richest people on the planet. We’re at that stage now, so the opportunity for investors is huge. But you could do both. You could invest in something like the SENS Research Foundation or the Buck Institute or one of those wonderful organizations that is trying to advance the cause, and at the same time invest in some of the companies that come out of those institutions. We’ve undertaken two joint ventures with the Buck Institute, we’ve made a couple of investments as a result of introductions by the SENS Research Foundation, including the organ regeneration program. So if you’re a sensible billionaire, you will be putting some of your funds to work in a combination of a charitable enterprise that drives the science and the businesses themselves that come out of those enterprises.

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A Review of HDAC Inhibitors as a Category of Drugs that Modestly Slow Aging

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HDAC inhibitors are a comparatively poorly understood category of drugs that act to modestly slow aging in short-lived laboratory species. As such, they most likely function through some form of upregulation of cellular stress responses, thus activating cellular maintenance processes that lead to improved cell and tissue function. That said, the chain of cause and effect leading from the known mechanism of action to that stress response upregulation is not clearly mapped. As for all approaches that slow aging via stress response mechanisms, we should remember that the effects on life span in short-lived species are much larger, relatively speaking, than those in long-lived species such as our own, even when the short term effects on the operation of metabolism are quite similar.

Calorie restriction is the canonical example of an intervention that upregulates maintenance processes, such as autophagy, that are activated under conditions of cellular stress. Calorie restriction can extend life span by up to 40% in mice, but certainly doesn’t add more than a few years to human life expectancy, even while producing significant benefits to health. Further, therapies that upregulate the same mechanisms as calorie restriction are typically only recreating a fraction of the effects on metabolism, and thus should not be expect to produce the same degree of benefits. This is all worth bearing in mind.

It has become increasingly clear that epigenetics, including DNA methylation, histone modifications, and chromatin state, play a crucial role in the aging process. For example, by assessing changes in DNA methylation patterns, a person’s age can be predicted within 5 years of accuracy. Histone modifications, including methylation and acetylation states, have been intimately linked to lifespan regulation. Together, these modifications dictate chromatin state, affecting both gene transcription and genome stability. Epigenetic changes occurring with age provide a tantalizing therapeutic target. In contrast to DNA mutations, epigenetic alterations represent reversible changes, offering the potential for a true “rejuvenating” therapeutic intervention. Of the various epigenetic alterations occurring with age, the influence of histone acetylation, a process balanced by the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs), on lifespan regulation has been the most characterized, mainly due to the advent of HDAC inhibitors from the cancer biology field.

The exact means by which HDAC inhibitors extend lifespan has not been fully resolved; however, a number of possible mechanisms can be envisioned. One possible scenario is that HDAC inhibitors reverse the natural age-related changes occurring in the histone acetylation landscape. This is the most simple explanation for their benefits, supported by the observation that many acetylation marks on histones generally decrease with age and in certain age-related diseases. A second possible mechanism of HDAC inhibitors is that they may affect histones and nucleosomes to directly activate transcription of pro-longevity genes. This is supported by observations that an endogenous HDAC inhibitor, β-hydroxybutyrate (BHB), can increase acetylation in the promoter of the pro-longevity transcription factor FOXO3a resulting in its increased expression, and indeed, BHB’s lifespan extending effects depend on HDAC genes.

A third possible mechanism through which HDAC inhibitors may increase lifespan is through hormesis. In this scenario, while high doses of HDAC inhibitors may be toxic, low doses would elicit activation of protective genes to regain homeostasis, ultimately improving function. This is supported by observations that flies treated with HDAC inhibitors show upregulation of heat shock protein chaperones, a class of genes that are usually upregulated under stress. A fourth possibility is that HDAC inhibitors may regulate lifespan by modifying the acetylation state of non-histone proteins, activating signaling cascades that promote longevity independent of histone modifications.

Despite the promising outlook of HDAC inhibitors for healthy aging, much work remains to be done to better understand their safety and how to minimize adverse side effects. Owing to their origins in the cancer biology field, many cell-type and dose-dependent negative effects of HDAC inhibitors on cell viability have been documented. Careful optimization of dose and drug pharmacokinetics should be made prior to pursuing any strategy in which HDAC inhibitors would be used as a prophylactic drug for healthy aging. More specifically, less-toxic versions of current drugs may be required. Understanding of the mechanism by which HDAC inhibitors extend lifespan is noticeably limited, and many mechanistic options remain. Deeper study of the specific modes of action of these compounds is necessary prior to their implementation as geroprotective compounds.


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Major Surgery in Later Life Produces a Minor Acceleration of Cognitive Decline

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Researchers here process statistical data to suggest that major surgery in later life accelerates cognitive decline. It would be interesting to compare data on serious injuries rather than surgery, as one of the possible mechanisms underlying this effect is a greater presence of senescent cells than would otherwise be the case. Senescent cells produce systemic chronic inflammation, and that is important in the progression of age-related neurodegeneration. Senescent cells are also generated in the course of wound healing, such as recovery from surgery, and some small fraction will always linger, failing to self-destruct or to be cleared from the body by the immune system. Thus we might expect severe injuries and major surgeries to produce some long term consequences to the pace of aging throughout the body. But this is pure speculation; the mechanism could just as well be something else.

Cognitive decline starts before conventional definitions of old age (often 65 years) and accelerates with aging and accumulation of comorbidities. Certain health events, such as stroke, can lead to profound changes in the cognitive trajectory such that there is a permanent “step change” in cognitive function. For 60 years a major concern has been that surgery might also drive long term changes in cognition. Yet studies investigating associations between surgery and long term cognitive outcomes have produced inconsistent results, with reports of cognitive harm, no effect, and cognitive improvement. Despite inconclusive evidence, considerable concern remains about the potential for surgery to induce cognitive impairment. Longer life expectancy implies an increasing number of surgical operations in older adults, hence a better understanding of the extent of any change in cognition after surgery is urgently required.

We use cognitive data from 7532 adults, investigating whether incident major surgical admissions are related to long term changes in the cognitive trajectory, using five waves of cognitive assessments spanning approximately 20 years, with adjustment for major medical admissions. To facilitate interpretation of results, we translate effect estimates to equivalent years of cognitive aging and relate changes to the effect of stroke, an event with an established impact on cognition. We primarily aimed to establish the mean population effect of major surgery on cognitive decline.

After accounting for the age related cognitive trajectory, major surgery was associated with a small additional cognitive decline, equivalent on average to less than five months of aging. In comparison, admissions for medical conditions and stroke were associated with 1.4 and 13 years of aging, respectively. Substantial cognitive decline occurred in 2.5% of participants with no admissions, 5.5% of surgical admissions, and 12.7% of medical admissions. Compared with participants with no major hospital admissions, those with surgical or medical events were more likely to have substantial decline from their predicted trajectory. In conclusion, major surgery is associated with a small, long term change in the average cognitive trajectory that is less profound than for major medical admissions. During informed consent, this information should be weighed against the potential health benefits of surgery.


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Most popular articles of 2019

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During the past 22 years of providing the latest research and information to help you make informed decisions regarding your health, it’s been interesting to see the trends and developments in medicine, science and technology.

It’s always a positive step to equip yourself with the most up-to-date information rather than relying on conventional medicine for your health decisions, and it’s our aim to provide it. In 2019, we offered articles and research on the following topics that were searched for the most often:

CBD oil


Ketogenic diet


Blood pressure

Vitamin D


Intermittent fasting


Magnesium L-threonate

One of my missions is to expose the entities in government, the media, corporate medicine (pharmaceutical companies) and academia bent on diverting you away from natural health — which is often far less expensive or even free. When you examine the motivations of those who do so, it may be less of a surprise to find that censorship is alive and well across every media platform.

You may be aware that it’s becoming more of a challenge as the war for information escalates. We’ve encountered serious roadblocks in the way we function as a website. Sharing our information relies heavily on the internet, but in recent weeks, the only way to locate Mercola articles is by adding “” to the search word(s) in question.

This puts us at a significant disadvantage in carrying out our objective of helping people gain or regain optimal health. Mercola’s content has been at the top of health search results for more than 15 years. Google’s June 2019 broad core algorithm update, as well as its restructured quality rater guidelines have effectively removed from Google search results, outlined in my two-part series: Google Buries Mercola in Their Latest Search Engine Update Part 1 of 2, and Part 2.

One of the most encouraging aspects of sharing my knowledge, passion and experience is the number of you who’ve taken advantage of the chance to learn more ways to be proactive with your health.

As in the past, continues to be a reliable source of health articles and nutritional advice, and my free natural health newsletter is packed with tips to help you live your healthiest life. We also carry top-quality wellness products. We’re also grateful for the many organizations that partner with us.

Below, you’ll find highlights of the top five articles of 2019, those which generated the “most shares.” For more in-depth information and the research associated with each of the five articles, make sure to click on the titles of each of them, listed below:

5. Low Cholesterol May Raise Your Alzheimer’s Risk The topic of cholesterol has been somewhat controversial in recent years due to a misunderstanding of what it is, what causes unfavorable numbers and, more importantly, what doctors often tell their patients about the implications if someone’s numbers are high — if you have high cholesterol, you probably have heard it from your doctor already: that the risk of stroke and heart disease is higher, as well.

What many people don’t realize, though, is that cholesterol is not only necessary but existent in everyone’s bloodstream and cell membranes. Without it, you couldn’t survive. It’s significant that in one review, elderly people with no history of Alzheimer’s had high levels of both LDL — also known as low-density lipoprotein or “bad” cholesterol — and HDL, often referred to as the “good” kind.

While your liver produces about 80% of what your body requires, the other 20% comes from the foods you eat. Between 20% to 60% of the cholesterol you consume is absorbed, but it varies from person to person; if you eat less, your body will make more.

In fact, LDL and HDL aren’t technically cholesterol at all. You could call LDL the “carriers” of cholesterol, as well as triglycerides (fat), proteins and phospholipids, while it’s more accurate to say HDL is the carrier of recycled cholesterol.

The fact that one-quarter of all your cholesterol resides in your brain is an indication that it’s an important aspect of neurological health, including your memories. Interestingly, studies indicate that low cholesterol levels increase your risk for depression and suicide, while higher levels are linked to better brain health.

You may find it helpful to know that ingesting healthy fats helps stave off neurological diseases like Alzheimer’s by 44%, while high carb diets increase your dementia risk by 89%. This is supported by experts who report that not having enough fat and cholesterol in your brain is a factor in dementia cases, and that one of the causes is attributed to a low-fat diet. In fact, a keto (high fat, low carb) diet is now an Alzheimer’s treatment.

4. Top 3 Dangers of LED Lights Controversy seems to be everywhere nowadays, and light bulbs again have become important to health discussions. In 2007, the rules for the types of light bulbs people could buy became a big issue due to a drive toward saving energy; phasing out incandescent bulbs in favor of light-emitting diode (LED) bulbs could save as much as 85%, according to The New York Times.1

Praised for fulfilling that goal, LEDs were singled out as the most energy efficient light bulb, lasting longer, radiating less heat than incandescents, and offering more durability. But in the push to save energy, factors like physical harm connected with LED usage have emerged.

The fact is, incandescent light bulbs are the closest to full spectrum analog natural sunlight. What apparently wasn’t known about LED lights when the government switchover was announced in 20072 is that they inflict damaging biological effects to people exposed to them. The top three dangers of LED lighting are:

Danger No. 1 — They deteriorate your vision as they emit excessive amounts of blue wavelengths and fail to counterbalance with regenerative frequencies. They have very little red in them and no infrared. When you’re exposed to higher blue light frequencies, they catalyze excess reactive oxygen species (ROS) formation, which damages your eyes in several ways. It also affects your sleep.

Danger No. 2 — They increase oxidative stress and potentially introduce cellular damage while causing mitochondrial dysfunction, metabolic disorder and cancer via suppressed energy production.

A molecule called cytochrome c oxidase, involved in mitochondrial energy production, creates adenosine triphosphate (ATP) or cellular energy, and ATP is needed to fuel all your cells. In fact, it’s crucial for survival — you can’t live without it. But LED light exacerbates chronic disease by suppressing ATP production.

Danger No. 3 — They inhibit your sleep. Electronic screens are a major culprit, but research shows that LEDs of all kinds suppress production of melatonin, and therefore sleep, which can damage your body in ways you may not be aware of. In fact, looking at an electronic device within an hour of going to bed can delay sleep for an hour or more, and TVs can’t filter out blue light. Installing a blue light filter on your TV screen can help.

3. Cell Tower Removed From Schoolyard Due to Cluster of Cancer Cases and Have You Seen the Safety Warning Hidden Inside Your Cellphone? School children in Ripon, California, being diagnosed with cancer sparked a new dialogue about whether electromagnetic field (EMF) radiation from Sprint cell towers was the culprit. Naysayers said the towers emitted less radiation than government standards prescribed, but the evidence remained.

If you’re familiar with EMFs, you know the U.S. Federal Communications Commission’s (FCC) guidelines are outdated, and worse, much of the research was bankrolled by the industries standing to make a profit from them. While denying any harm being done, Sprint agreed to move the towers, but that doesn’t negate the fact that wireless 5G towers are the next phase coming out, touted to make data speeds 100 times faster.

However, there are downsides, according to CBS News, which noted that “5G requires the installation of new equipment across the U.S. All of the companies that provide wireless service are building their own 5G networks.”3 In addition, the first 5G towers were slated for installation in several U.S. cities as of late 2018.

The industry plans to erect about 300,000 new antennas — about the number of cell towers put in place over three decades. Then they have to be not only closer to users, but while relatively smaller, much closer together, experts explain.

It gets worse: The FCC also announced that cities wouldn’t necessarily be able to choose the placement of the antennas. Lawsuits have ensued, including one involving the city of Los Angeles, and scientists worldwide are demanding a halt to the 5G rollout.

Proponents of ever-increasing wireless technology are thrilled with the prospect of the newest innovation, but health advocates are concerned about radiation. People whose lives are already disrupted by electromagnetic hypersensitivity and radiofrequency (RF) will suffer even more, and scores more will join them.

Tied to this is the problem that many people are unaware of the dangers cellphones pose: They should be kept at least 5 to 15 millimeters away from your head and body to avoid exceeding the safety limit for RF exposure, and the specific absorption rate (SAR) measurement of how much RF energy your body will absorb.

Numerous studies warn of potentially debilitating health problems, including heart arrhythmias, increased antibiotic resistance, suppressed immune function and pain.

2. Top Tips to Optimize Your Mitochondrial Health and Why Glucose and Glutamine Restrictions Are Essential in the Treatment of Cancer Most believe cancer is genetic, but it’s actually a metabolic disease. Genetic mutations in some cancers are due to defective energy metabolism in the mitochondria, known as the energy stations inside your cells. Keeping your mitochondria healthy significantly lowers your risk of developing cancer.

But many scientists and doctors don’t understand the science, or rather, they can’t accept this as the truth because it would change how they approach treatment. Further, neurodegenerative diseases such as Alzheimer’s, as well as seizure disorders, diabetes, obesity and high blood pressure are offshoots of mitochondrial dysfunction. Most major diseases treated by drugs can potentially be solved by a healthy diet, one that fights fat with the proper fuel.

All cancer cells use fermentation energy for growth. They ferment lactic acid from glucose in the cytoplasm. Fermentation involves not only lactic acid fermentation, but also succinic acid fermentation using glutamine as a fermentable fuel. Glutamine is a main fuel for many different kinds of cancers. Without glucose and glutamine, the cancer cells will starve, as they cannot use ketones. The simplest approach to cancer is to bring patients into therapeutic ketosis.

To do that, it’s necessary to restrict net carbs (total carbs minus fiber) and limit your protein. A ketogenic diet calls for 50 grams of carbs per day and limited amounts of protein (I recommend 1 gram per kilogram of lean body mass), as well as keeping your fasting blood sugar below 70 milligrams per day (mg/dL).

1. Fatty Liver Disease Is Triggered by Choline Deficiency Choline is an essential nutrient required for numerous physiological processes, from those in your brain and nervous system to those involving your cardiovascular system. Found principally in egg yolks, it’s also essential for liver function, including the prevention of fatty liver disease, and more specifically nonalcoholic fatty liver disease (NAFLD), the most common form of liver disease in the U.S.

This is significant because around 90 percent of the U.S. population is choline deficient, and it’s needed to move fat out of your liver. Without it, even healthy saturated fats can contribute to fatty liver. Choline minimizes liver fat regardless of the source. That said, for your liver to rid itself of excess fat, it has to have choline, and the more dietary fat you consume, the higher your requirement for choline.

The most significant culprit in NAFLD is too much fructose. Experts said 70 years ago that sucrose and ethanol could cause fatty liver and the inflammatory damage associated with it, and that increasing dietary protein, plus extra methionine and choline could mitigate and even prevent its effects.

The caveat is that carbs, unhealthy polyunsaturated fatty acids (PUFAs) and even healthy saturated fats can build up fat in your liver. And as popular as it is, corn oil is arguably the worst because it contributes to inflammation. It also contributes to issues with the important balance between omega-6 fatty acids and omega-3s. Despite warnings about egg yolks, eating them is an easy way to ensure sufficient choline in your body.

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Assessing Retrotransposon Activity and Senescent Cell Burden in Mice by Age and Tissue

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Retrotransposons are genetic sequences that can copy themselves to new locations in the genome. This activity increases with age, for reasons that are still poorly understood, and it is an open question as to the degree to which this is important as a cause of tissue dysfunction with aging. The arguments for and against are much the same as those for stochastic mutation of nuclear DNA to be a meaningful contribution to degenerative aging, with the most compelling model being the one in which mutations in stem or progenitor cells can spread widely in a tissue through their descendant somatic cells.

This open access paper is focused on assessing the growth in retrotransposon activity and the increasing burden of senescent cells with advancing age, the latter of which is of great interest given the development of senolytic therapies capable of selectively destroying senescent cells in old tissues. The two topics are not completely divorced from one another, as senescent cells have been shown to have higher retrotransposon activity, and this is necessary for the harmful signals that they generate, known as the senescence-associated secretory phenotype (SASP).

Tissue aging is the gradual decline of physiological homeostasis accompanied with accumulation of senescent cells, decreased clearance of unwanted biological compounds, and depletion of stem cells. Senescent cells were cell cycle arrested in response to various stimuli and identified using distinct phenotypes and changes in gene expression. Senescent cells that accumulate with aging can compromise normal tissue function and inhibit or stop repair and regeneration. Selective removal of senescent cells can slow the aging process and inhibits age-associated diseases leading to extended lifespans in mice and thus provides a possibility for developing antiaging therapy.

To monitor the appearance of senescent cells in vivo and target them, a clearer understanding of senescent cell expression markers is needed. We investigated the age-associated expression of three molecular hallmarks of aging: SA-β-gal, P16INK4a, and retrotransposable elements (RTEs), in different mouse tissues at three different stages in the aging process (1 month, 12 months, and 24 months). Our data showed that the expression of these markers is variable with aging in the different tissues. P16INK4a showed consistent increases with age in most tissues, while expression of RTEs was variable among different tissues examined.

Increased β-gal staining in cerebellar Purkinje neurons might reflect locomotor incoordination that is often associated with aged individuals. Increased β-gal staining also was observed in the hippocampus and substantia nigra, which are major brain regions associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, respectively. In addition, human aging is associated with reduced amounts of cerebrospinal fluid (CSF) and increased protein concentrations, which might be attributed to an aged choroid plexus. Thus, specific brain regions appear to be highly sensitive to an aging phenotype, which suggested that further investigations are warranted, especially for the choroid plexus and for the unique functions of CSF in healthy people and patients.

Similar to the brain, mouse kidneys demonstrated significant upregulation of the aging markers used in this study, especially in the renal cortex. It was surprising that the kidneys expressed a senescent phenotype earlier than any of the other organs included in this study. These findings might reflect the essential role of the kidney in the aging process. Previous studies have not focused on this relationship. The kidney is important in maintaining homeostasis of the body, suggesting that aging of the kidney is more likely to occur earlier than other organs and possibly the age-related decline of other organs might be a consequence of failure of the kidney to effectively eliminate circulating age-inducing molecules. Since elderly humans have less renal functional reserve and are more susceptible to chronic renal diseases, actions to preserve renal function might help to delay or alleviate aging-related consequences in the whole body.

We demonstrated that aging significantly influenced specific brain regions, the renal cortex, pulmonary bronchioles, and interstitial cells of the testes but had little or no effect on lung parenchyma, the liver, heart, and testicular seminiferous tubules. In conclusion, the gradual functional decline of peripheral organs might be a consequence of the aging brain or kidneys either through aging of neurons that influence these organs or through failure of the kidneys to eliminate age-associated molecules that occur due to environmental and genetic causes. Additionally, the age-dependent changes in RTE expression may be related to changes in function rather than directly associated with the aging process. The upregulation of RTEs in the mouse brain and kidneys might positively enhance the clearance of P16INK4a-positive cells.


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Targeted Editing of Gut Microbe Populates Reduces Intestinal Cancer Incidence

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The gut microbiome is influential on the progression of health, perhaps to a similar degree as regular moderate exercise. Age-related changes in these microbial populations can promote chronic inflammation and tissue dysfunction, though the direction of causation is still up for debate when it comes to many of the details of the relationship between tissue and immune issues in the intestine and an altered gut microbiome. Nonetheless, less desirable microbes undertake activities that can raise the risk of cancer resulting from inflammation of the intestines, occurring in conditions such as inflammatory bowel disease. Researchers here demonstrate that suitable adjustment of microbial populations in mice can lower the incidence of cancer in this circumstance. This is one application among what will no doubt be many cases in which the gut microbiome can be shifted in ways that promote better health over the long term.

People living with inflammatory bowel disease (IBD) have a three- to sevenfold higher risk of developing colon cancer. Researchers have now shown that precision editing of the bacterial populations in the gut reduces inflammation-associated colorectal cancer in mice. “The most significant finding in this study is that manipulating the intestinal microbiome is sufficient to affect the development of tumors. One could envision a time in which medications that change the behavior and composition of the bacteria that live in the gut will be part of the treatment for IBD.”

In addition to colorectal cancer, long-standing IBD is associated with imbalances in the bacterial species that line the gut. “Our intestinal tract is teeming with microbes, many of which are beneficial and contribute to our overall health. Yet, under certain conditions, the normal function of these microbial communities can be disturbed. An overabundance of certain microbes is associated with increased risk for the development of diseases, including certain cancers.” The strategy used in the study targets metabolic pathways that are only active during intestinal inflammation and only in some forms of bacteria, providing an Achilles’ heel for reducing their abundance. The current study builds on work that found the approach prevented or reduced inflammation in a mouse model of colitis, while having no obvious effect on healthy control animals with balanced bacterial populations in their guts.

“For example, most E. coli bacteria are harmless and protect the human gut from other intestinal pathogens such as Salmonella, a common cause of food poisoning. However, a subset of E. coli bacteria produce a toxin that induces DNA damage and can cause colon cancer in research animals. We developed a simple approach – giving a water-soluble tungsten salt to mice genetically predisposed to develop inflammation – to change the way potentially harmful E. coli bacteria generate energy for growth. Restricting the growth of these bacteria decreased intestinal inflammation and reduced the incidence of tumors in two models of colorectal cancer. Tungsten is a heavy metal and should not be used by anyone due to its toxicity. This is a proof-of-concept study that will guide us in developing future drugs with similar activity and less toxicity.”


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22 health tips to celebrate 22 years of

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To help commemorate 22 years of offering the most up-to-date health information available, I’ll review 22 currently top trending health topics based on our internal search results.

For each topic, you’ll find a short summary or overview. For more in-depth information, follow the hyperlinks provided in each section. You can also find a wealth of popular health guidance on “My All-Time Top 30 Health Tips” page.

No. 1 — Intermittent fasting

Timing your meals correctly can go a long way toward improving your health. A number of different intermittent fasting regimes have sprung up — some of which are more extreme than others — but all are based on the premise that you need periods of fasting, for 16 to 22 hours a day.

Among the latest is the one-meal-a-day or OMAD diet, which as the name implies involves eating just once a day.1 As noted in the paper “A Time to Fast,” published in the November 2018 issue of Science:2

“Adjustment of meal size and frequency have emerged as powerful tools to ameliorate and postpone the onset of disease and delay aging, whereas periods of fasting, with or without energy intake, can have profound health benefits.

The underlying physiological processes involve periodic shifts of metabolic fuel sources, promotion of repair mechanisms, and the optimization of energy utilization for cellular and organismal health …

In general, both prolonged reduction in daily caloric intake and periodic fasting cycles have the power to delay the onset of disease and increase longevity.”

For a long list of benefits linked to intermittent fasting, see “The Science Behind Time-Restricted Feeding.” My KetoFast protocol takes intermittent fasting a step further, providing a plan for how to safely perform a 42-hour fast once or twice a week, without triggering excessive detoxification symptoms.

No. 2 — Blood flow restriction (BFR) training 

Without a doubt, exercise is an indispensable health and longevity strategy, as it will allow you to leverage and optimize everything else that you’re doing. Contrary to popular belief, though, resistance training may actually be more important than aerobic exercise, especially for the elderly, as maintaining strong muscles plays an important role in quality of life and neurological health.3,4

Globally, sarcopenia or loss of muscle mass affects 10% of men and women over the age of 605 and up to 50% of those over 80.6 Building and maintaining muscle will also go a long way toward optimizing your metabolism and warding off insulin resistance,7 a primary driver of virtually all chronic and degenerative disease, including Type 2 diabetes and heart disease.

I’ve previously discussed how superslow resistance training can boost results by turning your workout into a high-intensity exercise. Another profoundly effective technique is known as Kaatsu training, or blood flow restriction (BFR) training. It’s probably the most effective type of resistance training out there, and it’s particularly beneficial for the elderly and athletes recovering from an injury.

For more in-depth details about how to do BFR, you can review my recently added instructions in our Exercise Guide.

You can also review an interview with Jim Stray-Gundersen, a leading proponent and teacher of BFR training in the U.S. In brief, it involves performing strength training exercises while restricting venous blood flow return to the heart (but not arterial flow) to the extremity being worked. I will be focusing on this topic with many more interviews and articles this year.

In a nutshell, by forcing blood to remain inside your muscle while it is exercising with low weights, you stimulate magnificent metabolic changes in your muscle that results in great improvements in strength and size with virtually no risk of injury.

A significant benefit of BFR training is that you can do strength exercises using just 20% of the weight you could maximally lift, while still reaping maximum benefits.

As a result, you circumvent the dangers associated with heavy weights. Blood flow restriction training can stimulate muscle growth and strength in about half the time, using about one-fifth of the weight, compared to standard weight training which makes it widely available to seniors.

No. 3 — CBD oil and/or full spectrum whole seed hemp oil

The medical benefits of cannabidiol (CBD) are now increasingly recognized, and we now know the human body produces endogenous cannabinoids and that this endocannabinoid system (ECS) plays an important role in human health by regulating homeostasis between your bodily systems, such as your respiratory, digestive, immune and cardiovascular systems.

CBD is nonpsychoactive, nonaddictive, does not produce a “high” and has few to no dangerous side effects. According to Project CBD, at least 50 conditions8 are believed to be improved by CBD, including pain, seizures, muscle spasms, nausea associated with chemotherapy, digestive disorders, degenerative neurological disorders such as multiple sclerosis and Parkinson’s disease, mood disorders, anxiety, PTSD and high blood pressure.

One of your healthiest options may be to use whole hemp oil rather than isolated CBD (from either hemp or cannabis), as CBD is just one of more than 100 different phytocannabinoids found in whole hemp, and the synergistic action between them is likely to produce better results.

According to phytocannabinoid expert Carl Germano, CBD alone cannot fully support your ECS. You need the other phytocannabinoids and terpenes, which are very complementary to the phytocannabinoids, as well. To learn more, see my interview with him, featured in “The endocannabinoid system and the important role it plays in human health.”

While the raw unprocessed plant could be juiced, processing will convert the cannabinoids into more usable forms. Germano suggests blending leaves, flowers and buds in a blender and storing the mix in the refrigerator for a day or two. “Probably, an ounce or two of raw plant would do the trick as a healthy plant beverage,” he says.

No. 4 — High blood pressure

In 2017, the American Heart Association (AHA) and the American College of Cardiology, along with nine other health organizations, changed the cutoff used to diagnose high blood pressure from 140/90 mm Hg to 130/80 mm Hg.9 Normal blood pressure is now below 120/80 mm Hg.

This slight shift increased the number of people diagnosed to include many who had previously been considered healthy. Usually, there are no warning signs or symptoms of high blood pressure. The only way to know for certain is to have your pressure measured.

Uncontrolled high blood pressure is the leading cause of heart disease and stroke and raises your risk of heart of kidney and heart failure.10 High blood pressure increases the workload on your heart muscle, which may result in heart failure and damage the arteries supplying the muscle with oxygen, leading to a potential heart attack.

High blood pressure may also damage small arteries, reducing the amount of oxygen delivered to your organs such as your kidneys and eyes. Over time, this may result in kidney failure11 and vision loss.12 Strategies to normalize your blood pressure include:

Avoiding processed foods (due to them being high in sugar, fructose, grains, partially hydrogenated oils and processed omega-6 oils)

Getting regular exercise, especially ones that increase nitric oxide. My new favorite exercise to lower blood pressure is blood flow restricted training, which you will hear loads more about this year

Optimizing your potassium-to-sodium ratio

Intermittently fasting

Reducing stress

Eating foods known to reduce high blood pressure, such as arugula, flaxseeds, beets, celery, olive oil and cooked tomatoes

Quitting smoking

No. 5 — How Google and Facebook are hurting you

In recent years, the privacy hazards and dangers to democracy and freedom of thought and speech posed by Google and Facebook have become increasingly apparent and well-recognized. In the summer of 2019, Google showed its true colors by implementing a highly-biased search engine update13 that buried Mercola search results, evaporating 99% of our Google traffic virtually overnight.

Google also has significant influence over urban development,14 health care15,16 and childhood education. In fact, Google’s influence over young children has been a concern for years.17

When you consider Google’s primary business is tracking, compiling, storing and selling personal data, by capturing children at an early age, it will be able to build the most comprehensive personality profiles of the population ever conceived — and there’s no opt-out feature for this data gathering.18

Personal data mining is also Facebook’s primary business. And while the U.S. Federal Trade Commission slapped Facebook with a $5 billion fine on July 24, 2019, to settle privacy breaches,19 this fine amounts to just one month’s worth of revenue,20 and Facebook’s stock actually rose immediately following the FTC’s announcement.21

What’s more, Facebook’s plan to integrate Instagram, Messenger and WhatsApp will make the company’s monopoly even more massive,22 giving Facebook truly unprecedented data mining capabilities. If you’re still in the dark about how much of yourself you’re giving away to these companies, and what the ramifications might be, see “What Kind of Information Does Google and Facebook Have on You?

No. 6 — Vitamin C protocol for sepsis

One of the most important medical discoveries in recent years is Dr. Paul Marik’s vitamin C protocol for sepsis — a progressive disease process initiated by an aggressive, dysfunctional immune response to an infection in the bloodstream, which is why it’s sometimes referred to as blood poisoning.

Each year, an estimated 1 million Americans get sepsis23,24 and up to half of them die as a result.25,26,27 Marik, chief of pulmonary and critical care medicine at Sentara Norfolk General Hospital in East Virginia, discovered a simple and inexpensive way to treat sepsis using intravenous (IV) vitamin C and thiamine (vitamin B-1) in combination with the steroid hydrocortisone28,29 — a discovery that may save tens of thousands of lives and billions of dollars each year.

His initial study30 showed giving septic patients this simple IV cocktail for two days reduced mortality nearly fivefold, from 40% to 8.5%. Sentara Norfolk General Hospital, where Marik works, has already made the protocol its standard of care for sepsis, and other hospitals are considering implementing it as well. Should you or someone you love get sepsis, knowing about this inexpensive treatment — and asking for it to be used — could be a lifesaver.

No. 7 — The cholesterol myth

After decades of research failed to demonstrate a correlation between dietary cholesterol and heart disease, the 2015-2020 Dietary Guidelines for Americans31,32 finally admitted that “cholesterol is not considered a nutrient of concern for overconsumption.”

A scientific review33 published in the Expert Review of Clinical Pharmacology in 2018 dismissed many long-held myths about cholesterol and the benefit of lowering it.

The paper presents substantial evidence that total cholesterol and low-density lipoprotein (LDL) cholesterol levels are not an indication of heart disease risk, and that statin treatment is of “doubtful benefit” as a form of primary prevention for this reason.

As a general rule, cholesterol-lowering drugs are not required or prudent for the majority of people — especially if both high cholesterol and longevity run in your family.

For more information about cholesterol and what the different levels mean, take a look at the infographic below. You can also learn more about the benefits of cholesterol, why you don’t want your level to be too low and ways to optimize your cholesterol level in “Cholesterol Plays Key Role in Cell Signaling.”

cholesterol levels

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No. 8 — Molecular hydrogen

Molecular hydrogen (H2) is a gas with very unique and selective antioxidant effects that specifically target the most harmful free radicals. It works primarily by improving and optimizing the redox status of the cell when needed.

As a result, you see improvements in superoxide dismutase, catalase and glutathione levels, for example. Not only does hydrogen selectively reduce the most toxic radicals, but it can help prevent an excess (which becomes toxic) of the free radicals from being produced in the first place. This is a very powerful prevention mechanism.

H2 also activates the Nrf2 pathway when needed. Nrf2 is a transcription factor that, when activated, goes into the cell’s nucleus and binds to the antioxidant response element in the DNA. It then induces the transcription of further cytoprotective enzymes such as glutathione and several others.

A landmark paper34 on molecular hydrogen came out in Nature Medicine in 2007, showing 2% hydrogen gas was effective at preventing brain damage from ischemia reperfusion and, as an antioxidant, has powerful therapeutic applications.

Hydrogen is the smallest molecule in the universe, and is neutral and nonpolar, which is why its bioavailability is so great. It does not dissociate into its electrons and protons when dissolved in water, so it will not alter the pH of water or your body and has nothing to do with the alkaline water concept.

To learn more about the details of how molecular hydrogen works, see “The Remarkable Benefits of Molecular Hydrogen,” in which I interview a world-class expert and researcher in this field, Tyler W. LeBaron.

According to LeBaron, more than 1,000 peer-reviewed scientific publications have collectively demonstrated that H2 has therapeutic potential in over 170 different human and animal disease models.

In fact, hydrogen is shown to benefit virtually every organ of the human body, and the reason for this is because hydrogen actually targets and mitigates the root causes of inflammation and oxidation.

No. 9 — Collagen considerations

Collagen is the most common and abundant of your body’s proteins, one of its primary purposes being to provide structural scaffolding for your various tissues to allow them to stretch while still maintaining tissue integrity.35

Collagen supplements allow for certain peptides to enter your bloodstream intact, before they’re broken down into their component parts in your digestive system, thereby benefiting connective tissues throughout your body.

Not all supplements are made alike, however. Laboratory testing36 has revealed many popular nonorganic poultry-based collagen and bone broth products contain contaminants, from antibiotics and prescription drug metabolites to parabens and insecticides — contaminants typically associated with concentrated animal feeding operations (CAFOs).

The results suggest CAFO animal byproducts are routinely used to make nonorganic poultry-based collagen products so, to avoid contaminants, it would likely have to be 100% organic.

What’s more, when you see a product is made from cow hides, it is best to ask questions about how that collagen is removed from the hides. Many tanneries use sulfuric acid and chromium salts during processing, which would negate any organic claims. To learn more about the benefits and potential drawbacks of collagen supplements, see “Collagen Benefits Skin and Joints, Study Confirms.”

My personal preference is to use a less denatured (unhydrolyzed) organic collagen supplement, as it has a more balanced amino acid profile. An even better choice would be to make homemade bone broth using bones and connective tissue from grass fed, organically raised animals. It’s the most natural approach of all and is, in my view, the best way to get the full range of benefits without the potential drawbacks.

No. 10 — Enzymes for optimal health

Your body secretes enzymes to catalyze biological reactions, making them vital to good health and longevity. Each organ has its own set of enzymes, and each enzyme has a different function. Enzymes can be broadly divided into digestive enzymes, metabolic enzymes and food-based enzymes, and there are two primary ways of using an enzyme supplement: digestively or systemically.

Taken with food, it will help digest the food. Taken on an empty stomach, the enzymes will pass through your digestive system and enter your blood circulation, providing systemic benefits.

While your body continually produces enzymes, certain factors can limit this capacity, such as aging (which lowers production), genetics (which may inhibit your ability to produce certain enzymes) and lifestyle choices such as diet, the amount of food you eat and whether or not you fast or smoke.

The healthier your lifestyle, the better your enzymatic activity will be, even without assistance from a supplement. For example, eating plenty of fresh, raw and/or fermented foods will supply your body with healthy enzymes. Sprouts are a particularly excellent source of live enzymes.

Fasting has also been shown to conserve enzymes. If you do not eat, you will not produce digestive enzymes, allowing metabolic enzyme production and activity to proliferate instead. A supplement can still be valuable, however, to counteract genetics, aging and a less than ideal lifestyle. To learn more, see “Enzyme Fundamentals.”

No. 11 — Moringa

Moringa is a plant with many similar benefits as broccoli. It’s part of the brassica family and is considered a vegetable,37 despite growing like a tree. Virtually every part of the plant is edible and has medicinal qualities, and most parts can be consumed either raw or cooked.

Globally, the leaves, roots, pods and flowers are most typically consumed.38 You can also harvest the plant as a microgreen. As noted in the mini-review “Health Benefits of Moringa Oleifera,” published in the Asian Pacific Journal of Cancer Prevention in 2014:39

“Moringa oleifera contains essential amino acids, carotenoids in leaves, and components with nutraceutical properties … An important factor that accounts for the medicinal uses of Moringa oleifera is its very wide range of vital antioxidants, antibiotics and nutrients including vitamins and minerals.”

Moringa is an excellent source of protein,40 fatty acids,41 beta-carotene, quercetin,42 flavonoids43 and an isothiocyanate called moringin,44 which like sulforaphane in broccoli has potent anti-inflammatory and cytoprotective effects.45

Like broccoli, Moringa has also been shown to have potent antibiotic activity against a wide variety of pathogens, including Escherichia coli, Salmonella typhimurium, Candida and Helicobacter pylori (H. pylori).46

Moringa, however, comes out on top (compared to broccoli) in terms of economics. It’s far easier to grow, even under challenging conditions, making it an excellent option in areas plagued by drought and other environmental challenges. The fact that you can eat more or less the whole tree in a variety of different ways also makes it an attractive option.

No. 12 — How to recover from arthritis

Rheumatoid arthritis (RA) is an autoimmune disease in which your body destroys your joints, and can be terminal. The remission rate is exceptionally low, and RA patients are typically treated with toxic drugs that in some cases can do more harm than good. Remission is possible, however, as demonstrated by Sarah Allen, a former patient of mine whom I interviewed about the details of her recovery.

It’s a popular article, and for good reason. RA is a complex and crippling disease for which conventional medicine has few answers. Food, it turns out, is a primary treatment. In Allen’s case, her genetic background suggested she may have an intolerance to wheat and gluten, which she eliminated. She also eliminated processed foods and sugars, focusing on whole foods and high amounts of fresh vegetable juice.

Other strategies included eating raw organic pastured eggs and organic meats, raising her vitamin D level, lowering stress and incorporating the Emotional Freedom Techniques, or EFT, to address the emotional component of the disease. Astaxanthin is recommended for pain relief related to inflammation, as is animal-based omega-3 fats.

Fermented vegetables provide valuable fiber and beneficial bacteria that help heal and seal your gut, which is an important part of the treatment of autoimmune problems. Low-dose Naltrexone can also be very helpful. It’s inexpensive and nontoxic, and while it is a drug and not a natural therapy, it is far safer than the other drugs typically used.

Lectins can also be problematic,47,48 and those with autoimmune disorders will often improve on a lectin-free diet. Lectins bind to carbohydrates and attach to cells that allow them to do harm as part of the plant’s self-defense mechanism against pests. Unfortunately, some may also cause trouble in humans.

Many lectins are proinflammatory, immunotoxic, neurotoxic and cytotoxic. Certain lectins may also increase blood viscosity, interfere with gene expression and disrupt endocrine function. You can see a list of the foods that are high in lectins that need to be avoided at Dr. Steven Gundry’s site.49 

No. 13 — Why 5G is a huge threat to your health

Electromagnetic field (EMF) exposures, which include AC electric fields from house wiring and corded appliances, AC magnetic fields from power lines and wiring errors, radio frequencies from smart meters, cellphones and Wi-Fi, and dirty electricity (transient voltage spikes as a result of switching mode power supplies) all have an effect on your biology.

EMFs have been linked to a wide array of health effects,50 including the creation of excess oxidative stress, opening your blood-brain barrier, allowing toxins to enter your brain, and damaging DNA in your nucleus and mitochondria.

It also impairs proton flow and ATP production, altering cellular function due to excessive charge, altering your microbiome and raising your risk for cancer. Importantly, EMFs also have neurological effects,51 and contribute to anxiety, depression, autism and Alzheimer’s.

All of these hazards are likely to exponentially increase with the implementation of 5G. One of the main problems with 5G — setting it apart from previous generations, i.e., 2G, 3G and 4G — is that it relies primarily on the bandwidth of the millimeter wave (MMW),52 known to penetrate 1 to 2 millimeters of human skin tissue.53,54

Research indicates that sweat ducts in human skin act as antennae when they come in contact with MMWs,55 causing pain.56 MMW has also been linked to eye problems,57,58 impacted heart rate variability (an indicator of stress),59,60,61 heart rate changes (arrhythmias),62,63 suppressed immune function64 and increased antibiotic resistance.65 To learn more, see “The 5G War — Technology Versus Humanity.”

Even without 5G, EMF exposure is a significant health hazard that needs to be addressed — especially if you’re already struggling with chronic health issues, as your recovery will be severely hampered if your body is constantly assaulted by these unnatural fields.

For a list of remedial strategies, see my interview with electromagnetic radiation specialist Oram Miller. My next book, “EmF’d,” which is scheduled to come out in early 2020, will be loaded with many more practical strategies.

No. 14 — Nose-to-tail carnivore diet

In a recent interview, Dr. Paul Saladino66 offered up a surprising twist on what constitutes a healing diet. A carnivore diet, virtually devoid of plant foods, he claims, may be helpful for those struggling with autoimmune disease.

As mentioned above, plant lectins can be problematic for some people, and that’s part of it. In order to be truly beneficial, however, it’s important to eat “nose-to-tail,” meaning you need to eat all parts of the animal, including organ meats and connective tissue. As noted by Saladino:

“It’s not just about eating steak. You’re really getting this incredibly diverse array of nutrients in the whole animal … You can get every single thing that we need.

It’s really interesting to kind of break it down and say, ‘You’re getting calcium in the bones. You’re getting copper to balance the zinc in the liver. You’re getting this B vitamin in the liver. You’re getting this B vitamin in the muscle meat.’

But what we find is that we have to eat the whole animal. If we just eat the muscle meat, we’re really going to be missing out on nutrients … I would argue further that animal-based nutrients are much more bioavailable than plant-based nutrients. They’re in the right ratio, which are incredible if you look at zinc, copper, calcium and magnesium.”

If you missed it and want to learn more about this novel theory, see “Health Effects of the Carnivore Diet.”

No. 15 — Glycine

Glycine is an inexpensive and readily available supplement with significant health benefits. Collagen can also be used, as it too contains high amounts of glycine. By inhibiting the consumption of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), glycine helps lower inflammation and oxidative damage.

Glycine will also help detoxify the herbicide glyphosate, which is now found in most conventionally grown and processed foods. Glyphosate is an analog of the amino acid glycine and attaches in places where you need glycine.

Importantly, glycine is used up in the detoxification process, hence many of us do not have enough glycine for efficient detoxification. To eliminate glyphosate, you need to saturate your body with glycine.

Dr. Dietrich Klinghardt recommends taking 1 teaspoon (4 grams) of glycine powder twice a day for a few weeks and then lower the dose to one-fourth teaspoon (1 gram) twice a day. This forces the glyphosate out of your system, allowing it to be eliminated through your urine.

No. 16 — B vitamins

B vitamins have gotten quite a bit of attention lately, with studies highlighting their importance for brain health and prevention of neurodegenerative diseases, migraines and psychiatric conditions.67

For example, vitamin B2 (riboflavin) has been shown to have potent neuroprotective potential, offering protection against both migraine and Parkinson’s disease by ameliorating oxidative stress, mitochondrial dysfunction, neuroinflammation, homocysteine neurotoxicity and glutamate excitotoxicity.68

Vitamins B6, B12 and B9 (folate, or folic acid in its synthetic form) have also been shown to reduce migraine disability.69 This same trio may also help prevent cognitive decline and protect against more serious dementia such as Alzheimer’s disease.70 As with migraines, a primary mechanism of action here is the suppression of homocysteine,71 which tends to be elevated when you have brain degeneration.

Deficiencies in B1, B2, B6, B8 and/or B1272,73 have been linked to neuropsychiatric symptoms, and symptoms of schizophrenia have been shown to significantly improve on high doses of vitamins B6, B8 (inositol) and B12.74

Aside from regulating homocysteine (which takes a toll on your brain structure and function), another reason why B vitamins have such a powerful effect on a wide range of brain disorders and psychiatric conditions has to do with the fact that they:

  • Have a direct impact on the methylation cycle
  • Are required for the production and function of neurotransmitters
  • Are required for the maintenance of myelin, the fatty sheath surrounding your nerve cells. Without this protective coating, nerve signals become slow and sporadic, which can lead to motor function problems, cognitive losses and changes in mood

B8 (inositol), specifically, aids cell communication, allowing your cells to properly interpret chemical messages and respond accordingly,75 while B6, folate and B12 (in combination with SAMe) regulate the synthesis and breakdown of brain chemicals involved in mood control, including serotonin, melatonin and dopamine.

This is why a deficiency in one or more of these B vitamins can trigger symptoms of depression. High doses of B6, B9 and B12 in combination may also offset damage caused by air pollution.

No. 17 — Choline

Choline deficiency has been identified as a major contributor to liver disease, including nonalcoholic fatty liver disease (NAFLD), as it’s required to move fat out of your liver.76 Chris Masterjohn, who has a Ph.D. in nutritional science, has suggested the rise in NAFLD is largely the result of shunning liver and egg yolks77 — two foods exceptionally high in choline.

According to a study78 published in the journal Nutrients, only 8% of U.S. adults are getting enough choline — including only 8.5% of pregnant women. Among egg consumers, however, more than 57% meet the adequate intake levels for choline.

Based on the outcomes, the study authors concluded that “it is extremely difficult to achieve the adequate intake for choline without consuming eggs or taking a dietary supplement.”79

Choline also helps keep your cell membranes functioning properly, plays a role in nerve communications and prevents the buildup of homocysteine in your blood, which is good because elevated levels are linked to heart disease.

It also helps reduce chronic inflammation and enables your body to make the brain chemical acetylcholine, which is involved in storing memories. In pregnant women, choline helps prevent birth defects such as spina bifida, while also playing a role in your baby’s brain development.

No. 18 — Beta-glucans

Beta-glucan is a polysaccharide — a type of fiber — found in yeast, algae, bacteria and fungi, known for its immune-boosting and cancer-fighting activities. One of the most common food sources is mushrooms. Shiitake, maitake and oyster mushrooms are all good sources.80

Importantly, beta-glucans enhance natural killer (NK) cell activity and function,81 and research82,83 shows that if you have enough NK cells in your system, you will not contract influenza.

According to the authors, the results clearly showed those having 10% or more NK cells remained well, with no flu symptoms, while those whose NK cells were below 10% became ill. Several other studies have also shown beta-glucans offer powerful protection against cold and flu. To learn more, see “Best Nutrients for Cold and Flu Season.”

No. 19 — Quercetin

Another potent antiviral is quercetin. Influenza strains are not the only viruses that succumb to quercetin, though. Studies have confirmed its effectiveness against a wide variety of viruses, including:

  • Herpes simplex virus type 1, polio-virus type 1, parainfluenza virus type 3 and respiratory syncytial virus84
  • Dengue virus85
  • Hepatitis B86 and C87

Its antiviral effects are attributed to three main mechanisms of action: Inhibiting the virus’ ability to infect cells, inhibiting replication of already infected cells and reducing infected cells’ resistance to treatment with antiviral medication.

Found naturally in apples, plums, red grapes, green tea, elder flower and onions,88 the quercetin in these foods may also ameliorate obesity, Type 2 diabetes,89 circulatory dysfunction, chronic inflammation, hay fever and mood disorders.90

No. 20 — Ashwagandha

Ashwagandha is a powerful adaptogenic herb that helps your body manage and adapt to stress by balancing your immune system, metabolism and hormonal systems.

Its anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoietic and rejuvenating properties makes it one of the most important herbs in Ayurvedic medicine. Importantly, a number of studies have shown it can treat several diseases and disorders better than medications, without all the side effects.

For example, research suggests taking 300 milligrams (mg) of a highly concentrated full-spectrum ashwagandha extract twice a day for 60 days may result in significant reductions in stress.

Other studies have shown ashwagandha has antitumor and blood production (hemopoietic) capabilities, and benefits the cardiopulmonary, endocrine and central nervous systems, all “with little or no associated toxicity.” For a long list of demonstrated health benefits, see this review on Ashwagandha.

No. 21 — Treating autoimmunity

By definition, autoimmunity refers to conditions in which your immune system malfunctions and starts attacking otherwise healthy or normal cells or nutrients. The presence of autoantibodies in blood tests is one diagnostic indication that you have an autoimmune disease.91

Autoimmune diseases can be difficult to treat through conventional means. However, many will find improvement through lifestyle changes, starting with diet. With some disorders, such as Hashimoto’s — a thyroid autoimmune disease — you will need to be on a gluten-free diet,92,93 as the gluten molecule looks like thyroid hormone, triggering an immune attack, thereby worsening the condition.

Optimizing your vitamin D is crucial for all autoimmune disorders, as vitamin D influences genes related to autoimmune diseases, including MS and Crohn’s diseases.94 Vitamin D also helps optimize your immune function in general.

Another dietary factor that can wreak havoc on those with autoimmune diseases is plant lectins, discussed above. To learn more about how lectins impact autoimmune diseases, see my interview with Dr. Steve Gundry in “Limit the Lectins.”

No. 22 — Indole 3 Carbinol (I3C)

Cruciferous veggies contain several plant compounds that are important for optimal health, including powerful chemoprotective compounds. In addition to sulforaphane, another important chemoprotective phytochemical is indole-3 carbinol (I3C),95 which in your gut is converted into diindolylmethane (DIM).

DIM in turn boosts immune function and, like sulforaphane, plays a role in the prevention and treatment of cancer.96,97 I3C also works by activating a protein called aryl hydrocarbon receptor (AhR), which communicates with immune and epithelial cells in your gut lining, thereby helping to reduce inflammation caused by pathogenic bacteria.

AhR also helps stem cells convert into mucus-producing cells in your gut lining. These cells also help extract nutrients from the foods you eat, all of which translate into improved gut function and health.

Have a look at Nitric Oxide Supplement and Heart health.

Read More

Fight Aging! Newsletter, August 12th 2019

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  • An Interview with Reason at Undoing Aging 2019
  • The Potential of Senolytic Therapies to Treat Chronic Kidney Disease
  • The Implications of Greater Amounts of Remnant Cholesterol in the Bloodstream
  • Reviewing Progress Towards Regenerative Therapies for Age-Related Hearing Loss
  • The Present Popularity of Epigenetic Reprogramming to Treat Aging
  • An Interview with Daniel Ives of Shift Bioscience
  • The Gut Microbiome Changes Over the Course of Aging
  • MicroRNA miR-122 is Important in Improved Mitochondrial Function Resulting from Calorie Restriction
  • Increasing NAD+ to Improve Mitochondrial Function Slows Age-Related Hearing Loss in Mice
  • Comparing the Metabolomic Signature of Aging in Mice and Naked Mole-Rats
  • The Inflammatory Feedback Loop Produced by Senescent Cells in the Aging Heart
  • DGCR8 Overexpression Attenuates the Accumulation of Senescent Cells with Age
  • Cytomegalovirus in the Immunology of Aging
  • Even Low Levels of Infection Can Cause Cardiac Dysfunction in Older Individuals
  • A Comparatively Simple Approach to Improve Engraftment of Transplanted Cells

An Interview with Reason at Undoing Aging 2019

Much of the proceedings at Undoing Aging in Berlin earlier this year were recorded, but of course it takes a few months for everything to process through the queue. I briefly escaped from the conference for an ad hoc, unstructured discussion with Adam Ford of Science, Technology, and the Future, who, like the Life Extension Advocacy Foundation folk, was interviewing as many people as he could during the event. It wound up a monologue on topics that were at the top of my mind at the time, particularly the present state of funding and the transformation of our community from a primary focus on advocacy and academic research to one in which a great deal of important work is now carried out in startup companies, and the utilitarian ethics of treating aging as a medical condition. The resulting video is now up at YouTube, and is here accompanied by a transcript for those who prefer text.

I’m Reason. I’ve been around in this community for quite the long time, going on I guess twenty years now, rather shockingly. I seem to have become old in my own lifetime; I’m not as young as I look, unfortunately. I run Fight Aging!, the blog, which I’ve used as a platform for advocacy for some time, the aforementioned going on twenty years, though more like fifteen now for that site. Recently, last year, I cofounded Repair Biotechnologies with Bill Cherman to actually jump into the industry and do some things. Prior to that I was investing as an angel in a few biotech startups focused on aging, where I felt it was a better choice than giving to the SENS Research Foundation or other groups to do the research, because companies have the chance to attract a great deal more funding more rapidly than non-profits do, unfortunately – that is just the way of the world.

That is very much the transition of our community right now. And as that happens, I think it becomes much more important to think about why the hell are we doing this thing? Sudden influxes of vast amounts of funding are consequential. There are several hundred million funds right now, focused on longevity, and there will be more next year, because it is a land rush right now. If you lose sight of why you are doing this, and thus what is the most effective approach, then you wind up with a bunch of idiots doing stupid things that won’t work, and the upshot of that is that funding will be wasted. It is to a certain degree unavoidable, I mean look at the dot com era; every new industry has its peak of hype, a bunch of stupid things happen, a bunch of charlatans come in and take funding from investors who don’t know any better. It will happen, but I think that those of us who are here now, and have been here in this community, have something of a duty to try to reduce the size of that problem, down to some nominal minimum, to the degree that that is possible to achieve.

So why do we do this? The fundamental philosophy of the problem is that death is bad. Suffering is bad. That death is bad is the more debatable of those two. It is quite possible to construct an ethical position in which we say it is fine to be dead, you didn’t exist for quite a long time prior to existing, and you will not exist for quite a long time after you cease to exist. That is the way of the universe; the Stoics were good with this position. But I think it is very hard to argue that suffering is acceptable, at least above the sort of “maybe I should get out of bed and do something today” level of suffering needed to motivate the human animal to go and do something constructive. Anything much more than that level of angst I think should go away – and certainly that includes the level of pain, physical decrepitude, loss of function, and horrible things happening to the people around you that comes with aging. That should go away.

The world just hasn’t quite got there yet in terms of thinking about this in the right way. People think about malaria in the right way. Malaria is something like one six hundredth of the cost to humanity of aging, depending on how you want to measure all the little fripperies around the edges. So if we really feel up in arms about malaria, willing to spend billions on getting rid of it, which some people clearly are, then we should be spending trillions on getting rid of aging. We should be, but we are not, and that is why the advocacy community came into being. We have this weird mismatch between our capabilities and our goals. The world is a crazy place, I think everyone acknowledges that; there are many, many insanities that the human condition contains, be that politics, be that the way that some people like peanut butter, pick your poison. The present relationship with aging is just another one of these insanities: the world is insane with respect to aging, because accepting aging is insane. Why would anybody accept that he or she is going to crumble and die, and not want to do something about it? Plain, basic utilitarianism says that we should do something about it if we can do something about it. And we can do something about it!

So is the population of the world asleep at the switch because next to no-one realizes that we can do something about it? That will change pretty soon. Senolytics will wake up everybody. What if you can take one pill that makes your arthritis go away? That is basically what senolytics will do, when they are truly effective. The ones we have right now, that are available right now, appear to be fairly good at getting rid of arthritis, based on the results of trials yet to be published. Once this realization happens, I think there will be an interesting phase change. People will start to somewhat wake up from this business of “oh well, aging is just a fact of life, wherein we’re all going to die horribly, let’s just get on and try to paper over that.” So no, instead let us go full on utilitarian and try to do something about it. That is essentially the philosophy of action here. It is that aging is so terrible that there is really no amount of effort that humanity could spend on this problem that would be too great. Of course we’re so far away from anything that even approaches a reasonable amount of effort, given the level of death and suffering caused by aging, that for the foreseeable future we can keep on advocating and building hundred million funds. If investors build another hundred of those hundred million funds, that would be a nice start, but by no means the right amount of funding in order to reasonably address the problem, given what it actually costs.

The cost is enormous, and, sadly, most discussions about aging, when they do get going, really skate over the utilitarianism of it in favor of “wow, we’re spending a lot of money on entitlements, we need to do something about this.” That latter expression seems to be what passes for ethical thought in policy circles these days. It is a matter of “well, we’re spending a bunch of funds, we should find a way to stop doing that.” Then of course, the nihilists seems to be mostly in charge now, because their idea of spending less is to not treat old people for their conditions, rather than building rejuvenation therapies that stop old people from getting those conditions. As I said, it is insanity. This really just needs to change. So this is why the advocacy, and now that we’re at the point at which funding can be raised for startup companies working on rejuvenation biotechnologies, these startups are just another form of advocacy, really, if you look at the bigger picture. We’re not building therapies because we can do something with our small slice of the pie of aging, we’re building therapies because if we show people that we can do something with our small slice of the pie of aging, then soon enough there will be another hundred companies over the next decade, working on their small slices. People will see success and attempt to replicate it themselves.

There are a hundred, two hundred, three hundred programs out there languishing in the research community that could be turned into companies, turned into therapies, doing useful things in and around aging. As you know, the research community is just not good at raising funding. They are not good at translating their research to the clinic. They are poor at a lot of things other than just advancing the science. I think it falls to the rest of us, where “the rest of us” means anyone who might be an entrepreneur, or in venture capital, or an advocate, to set forth and sift through these programs, the output of the scientific community, and say “look, we should do something with these things.” If the research community isn’t pushing a program forward, well, this is a time in which anyone can wrap a company around a project, say “I think we can do something with this,” go to venture capital and get a few million in seed funding.

That will be the case for the next twenty years, on and off, as the market cycles up and down. So we should have a thousand startup companies working on a thousand projects related to aging. While there are only seven categories of fundamental causative damage, per SENS, some of those categories are very, very broad in terms of their little individual components. We have to fix all of lipofuscin, and we don’t even have a good catalog of everything that is in lipofuscin, just the major pieces of it. We have to get rid of all the amyloids, and that is a good few dozen projects right there. Replacing aged stem cells: a different cell population, different recipes for therapy for every tissue. And so on and so forth all the way down the list.

Then after we’ve worked through the SENS list of causative damage as it exists today, there will be all the things about aging that are problematic but are hidden by the fact that people presently die before they become problematic. Such as nuclear pore proteins in long-lived neurons. Some of those molecules never change after they are initially created. It is the same molecule for your entire life, and if it gets damaged, well, that is kind of a problem. How do we build the nanotechnology to go fix our nuclear pore proteins? That is a problem that no-one should much care about today, because there are fifty other things that will kill you before that will become an issue. But it will become an issue, eventually. If we come to live to 150, I’m willing to believe that your nuclear pore proteins becoming corroded and corrupted and reacted with is actually a serious issue, at least in neurons.

We can in principle replace everything except the brain. So the worst case scenario for the ultimate future is that they open your skull, take out your brain, and put it into a new body. I’m sure it will actually be somewhat more sophisticated than that, but this is just a thought experiment – what is the most radical thing you can make work in terms of replacement, in principle? That is moving the brain to a new body. What will probably happen instead is that your new body will be rebuilt from your old body: regeneration and rejuvenation by delivery of cells and therapies and control over cell behavior. But the brain itself? A really challenging problem, because you have to fix it without breaking it. I think we are along the way towards understanding the mechanisms to target for the early, preventative reductions in inflammation, to avoid supporting cells in the brain going crazy, to get rid of the protein aggregates. To try to keep things the way they were during your 30s. But that is just a starting point. There is so much to do after that. It is a big project. When I say trillions in funding, I’m serious. This is a very big thing, this is reinventing architecture when you are a caveman, going all the way up to the Renaissance, and building huge palaces. That is the scope of the project for us. I don’t think it will take as long as it took the cavemen, but I think that we’re definitely in for the long haul. To the extent that we can incrementally build meaningful rejuvenation therapies along the way, then many of us will also be in for the long haul, and this turns into someone’s life’s work. That life might be rather long.

I don’t know how long people will live. I am a late 40s individual, and if you can just run the thought experiment of the biotechnologies that will be available to me in my 80s, I won’t look anything like an 80 year old person today. I will have no chronic inflammation; no senescent cells; probably no cross-links in my body; my stem cells will have been replaced; my immune system gardened; and so on and so forth through a long list of treatments that are going to happen in the next few decades, and are very plausible right now. So you can add these things up and say, right, if an 80 year old has no inflammation, no senescent cells, no cross-links, no atherosclerosis, what does that do to health? Do you still look like an 80 year old? Can you go run a mile? No-one knows, and we get to find out by doing it. That is the great adventure.

The big problems in aging are all comparatively simple to solve, and it is all benchwork in the lab to get your programs going. You don’t need the massive computational, big data, machine learning projects that are popular right now. The only place where present artificial intelligence might be useful is in improving the state of small molecule drug discovery, and my belief is that small molecule drug discovery will go away, largely, in favor of gene therapy. So maybe your AI is looking for genes or proteins that are of useful effect, but the present process of finding genes that have useful effects is not terrible. It is having good results. The upshot is, ok, where do you use AI in this process outside of small molecule development? And I don’t see anything in which AI is absolutely necessary, useful in any way other than incrementally improving the infrastructure, reducing costs. Targeting senescent cells with senolytics, that is where small molecules might be useful, but the best projects there don’t involve small molecules. Dealing with mitochondrial DNA damage? No, that is benchwork, and it seems unlikely that small molecules can do anything meaningful there – that is gene therapy territory. Stem cells? Again, it is just a matter of developing the methodologies that can lead to successful therapies, and deep down under that development, you find a role for AI in anything where there is a lot of data to be analyzed, but it is only incremental improvement in cost and efficacy.

Infrastructure makes the world turn, and incremental improvement is not to be sneezed at, but it is just a part of the technology background. You can’t just jump up and say “we’re going to do AI for longevity”, no. You are going to do AI for biotechnology in general, and biotechnology is then applied to longevity. So AI will vanish into the tool space. It won’t be a major category that is up there on its own in the fight against aging. Right now it is because it is novel and because investors throw funding at AI like there’s no tomorrow, and entrepreneurs and scientists follow the funding. So you get In Silico Medicine, for example, and they are doing small molecule discovery AI, which is what most other people are now following on to do nowadays, because that is where the funding is in the present phase. But I think this will just fade into the background, it will be another tool in the toolkit. It isn’t exciting, it is not category changing. It is an incremental advance, using computers a little bit more to help you do things when there is a lot of data involved.

Let’s talk about Effective Altruism. That community is doing smart things, in the sense that Big Philanthropy is thoroughly corrupt, and one should ask the question: if I want to do good in the world, versus conning myself into thinking that I did good in the world, what should I in fact do? You don’t give to the Red Cross, because the Red Cross is a thoroughly corrupt organization. The same for most large entities in philanthropy; they have enormous overheads, and most donated funding doesn’t go to the projects you would want it to go to. The Effective Altruism movement in that sense is great, and a very overdue examination and critique of philanthropy as a whole. Secondly, if the effective altruists can find convincing ways to convince high net worth individuals to actually give sensibly, this will be a good thing. I suspect that reason many of high net worth individuals don’t give sensibly is because they have absolutely no idea how to do good, and it is a big project to figure out how to do good at scale. If Effective Altruism can lead to more people in the high net worth category putting their funds into projects that actually have a good chance of improving the human condition, then that is a public good.

The third strand is obviously that the Effective Altruism community includes people who are quite concerned about which projects to fund from a utilitarian point of view, and to the extent that anyone takes even a cursory look at aging, it is obviously the case that aging is far worse than anything else that happens anywhere. Pick your favorite cause in the third world, and I can tell you that those people are suffering more from aging than from the target of your favored cause. Even for war, even for famine, it is still the case that aging is much, much worse. This is a sad thing, because we could be dealing with all of these issues, but when it comes to prioritization, yes, if you want to solve famine because it is terrible and causes people to suffer, then you also be willing to work on solving aging in that same population, because it causes a far worse outcome to far more people. So the Effective Altruism community should logically work its way to advocacy for the treatment of aging as a medical condition, because it is undeniably the case that it is the worst problem facing humanity, and it is the most cost effective point of intervention to reduce suffering and death in the world. Even when intervening in tiny ways, the outcome is an enormous return on philanthropic investment in the cause.

So I think that the effective altruists do good, and I think that there are not enough of them, and I think that they are not talking about aging to the degree that they should. But they are coming at it largely from an outsider perspective, and except for a few, they don’t understand the science, they don’t understand the degree to which rejuvenation is possible. Effective Altruism is a young movement, it has a way to go yet, but it has the potential to be very important. We shall see how it develops. In terms of our community engaging with effective altruists, it is all just advocacy at the end of the day. To the extent that the aging research and development community needs funding, then we set forth and engage the effective altruists to the extent that they have funds, or can influence sources of funding. If it is more effective to talk to effective altruists, then we aging advocates will do that, trust me.

That might be challenging as an argument right now, as right now it is clearly more effective to talk to venture capitalists, because they are very incentivized to put funding into these projects. Very large amounts of funding, in fact, to the point at which it would be very hard to raise that level of funding through any sort of philanthropic program. Unless of course you are talking to high net worth individuals. But convincing high net worth individuals to go and put funds into work on treating aging is Effective Altruism, whether or not you are cloaking it in that name. Certainly, I and others are guilty of poking high net worth individuals to say “have you thought about this a little bit? Do you want to get old? You can do something about it. So go do something about it.” But it is an incremental process. You can’t just flip a switch and have all of the trooping masses of the Effective Altruism community go off and spread the desired message. So we shall see. It will go where it goes.

There is an enormous waste right now in development and deployment of ineffective ways to treat age-related disease, those that don’t target the causes of aging. Further it will cost a great deal to develop functional rejuvenation therapies that do target causes of aging. But if you look at the enormous amounts that are spent on merely coping with the consequences of aging, then making it go away is highly efficient. But of course it is not just about funding and cost, it is about effective reduction of suffering. Funding spent on anti-aging research is an enormously cost-effective way to reduce suffering, providing it is spent on the right anti-aging research, rather than the programs that are not likely to produce more than a small effect. So mTOR inhibitors are great compared to previous technologies for dealing with age-related diseases, because they influence a lot of processes, but the effect size is really not large in the grand scheme of things. If you are going to put funding into developing mTOR inhibitors, then fine, that is happening, then you should spend that same level of funding on aspects of the SENS program that can actually repair underlying damage, rather than trying to tweak the body to be a little more resilient to damage. People taking mTOR inhibitors are still going to die on the same schedule as the rest of us. That aren’t that much more resilient. People with senescent cells removed, on the other hand, well, who knows. We will see what that does to life span. I think that the pensions and insurance companies are going to be in for a rude awakening. Personally, I think that five years of additional life is not an unreasonable guess, and that will break a lot of insurance companies if they haven’t prepared successfully.

Regarding what will convince the world that meaningful progress is happening and further meaningful progress is possible, I think that recent developments in the laboratory, particularly around senolytics, are convincing to scientists. That is helpful. But I don’t think that it convinces the world at large in a useful way. Things have to leave the lab for that to happen. The thing about senolytics is that even those initial compounds available now seem to be quite good at making a sizable impact on quality of life in older people, and possibly for autoimmune diseases, and a bunch of other things. To the degree that we can say “guys, we’re giving you a rejuvenation pill, your arthritis is probably going to go away” and then if even half of the patients lose their arthritis, or their symptoms are greatly minimized, and they lose their other inflammatory conditions, and we turn back early Alzheimer’s disease – and all of these are plausible things that senolytics should accomplish, based on the mouse studies – then if that happens, then suddenly rejuvenation therapies are a real thing, and people can stop saying it is impossible to rejuvenate humans. Then we can go from there to explain that this is just one part of a larger program. We’re just doing one tiny thing, and not even that well, and look how good it is.

Senolytics will be the point at which an awful lot of things change. The early stages are happening right now. The self-experimentation community is doing interesting things with senolytics. Once the first studies that actually have large effects are published, it will be hard for regulators to keep these early senolytic drugs out of peoples’ hands. There are 60 million people in the US alone who would benefit from senolytics because they are old enough to have conditions that are inflammatory. This should happen. It will happen. And that would be the moment, I think. Senolytics, not anything else. Aging is a huge burden. Effectively treating aging will solve many problems. Old people are old people because they are aged. If you rejuvenate them, then they are no longer old. They will have a better time of it, and if you have an aging population of 80 year olds who are physiologically like 65 year olds, then you have an aging population of 65 year olds, effectively. After that it is very easy.

The Potential of Senolytic Therapies to Treat Chronic Kidney Disease

Senescent cells are a cause of aging. While near all senescent cells are destroyed shortly after entering that state, either by their own programmed cell death processes or by the immune system, the few that linger accumulate over the years to cause considerable harm. While it is true that even in late life senescent cells are far outnumbered by non-senescent, functional cells, senescent cells secrete a potent mix of inflammatory and other signals known as the senescence-associated secretory phenotype (SASP). The SASP disrupts tissue function, encourages nearby cells to also become senescent, and produce a state of chronic inflammation that accelerates many age-related conditions.

On the bright side, this means that near all age-related conditions can be turned back to some degree by the targeted removal of senescent cells, using senolytic therapies. The more such cells that are destroyed by a treatment, the larger the benefit. Since this produces such a broad range of beneficial effects, and there are only so many scientists in the world, the research community has yet to fully investigate even all of the most compelling, urgent uses of senolytic treatments to reverse specific age-related disease, let alone all of the other, lesser opportunities.

Today’s open access paper on the prospects for senolytic therapies to effectively treat chronic kidney disease is an example of the sort of work we’ll be seeing on a regular basis in the years ahead. Research teams will make slow inroads on assessing the use of senolytics as a rejuvenation therapy that can benefit patients with age-related condition A, B, or C, and so forth through a long, long list of diseases. It is a measure of just how new this field is, assessed in the grand scheme of things, that even the most widespread and severe conditions such as chronic kidney disease, those with no good therapeutic options at present, and wherein senolytic treatments might plausibly turn back much of the disease, are still not well investigated.

Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools

Chronic kidney disease (CKD) is defined by the persistent loss of kidney function and currently affects approximately 13.4% of the global population. The progressive nature of CKD often leads to end-stage renal disease (ESRD), requiring renal replacement therapy. To date, there are no curative therapeutic options for CKD/ESRD. An as yet untreatable final common pathway irrespective of the etiology in CKD is kidney fibrosis, characterized histologically by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Numerous compounds directly targeting factors involved in fibrosis driving pathways are currently being studied with varying results. Apart from the use of the renin-angiotensin-aldosteron pathway interfering agents such as ACE inhibitors or angiotensin receptor blockers to reduce the progressive remodeling of renal parenchyma, no therapeutics that can address the pathophysiological mechanisms underlying CKD are used clinically. However, increasing effort is currently put into investigating the efficacy of targeting senescent cells during renal disease.

Aging is associated with the decline of kidney function. During aging, increased renal p16 expression is most notably seen in tubular epithelium and to a lesser extent in glomerular (podocytes and parietal epithelium) and interstitial cells. Changes in p16 were more pronounced in the cortex compared to the medulla. In rodents, the amount of senescent proximal tubular cells increases with age, whereas no increase of senescent cells is seen in the glomeruli. Renal tubular cell senescence correlates with tubular atrophy, interstitial fibrosis, and glomerulosclerosis. Furthermore, the removal of senescent tubular cells leads to decreased glomerulosclerosis.

Eliminating senescent cells through transgenic depletion and pharmaceutical inhibition reduces kidney dysfunction and long-term kidney injury in experimental models of kidney damage, obesity-induced metabolic dysfunction, and during aging. These promising results have spurred interest in the development of clinically applicable therapeutic compounds that target senescence-associated pathways. Eliminating senescent cells (dubbed as senolysis) is just one of the various potential interventional approaches to target the adverse effects of cellular senescence (so-called “senotherapy”), including the prevention of senescence, modulation of SASP (termed senomorphics), and stimulation of immune system-mediated clearance of senescent cells.

The removal of senescent cells with so-called “senolytics” may be the most feasible and most attractive approach for clinical application, as the prevention of senescence and modulation of SASP would require chronic treatment with prolonged exposure to therapeutics. Several chemotherapeutics and checkpoint inhibitors currently used in daily oncological practice show senolytic properties. However, the applicability of such senolytic compounds for the treatment of renal diseases has hardly been investigated.

Research regarding senescence in the kidney has pointed to the proximal tubular epithelium as the culprit, and the removal of senescent tubular epithelial cells is therefore a promising approach to the attenuation of fibrosis in CKD. Due to the specific nature of proximal tubular epithelium, several specific targeting options are available, by which therapeutic drug efficacy can be potentiated and side effects can be reduced. Repurposing senolytic drugs that have been tested in clinical trials for other, mostly oncological, indications by functionalization for targeted delivery is a promising method to make a fast translation to clinical nephrology practice.

The Implications of Greater Amounts of Remnant Cholesterol in the Bloodstream

Atherosclerosis is a condition in which fatty lesions form to narrow and weaken blood vessels. It causes a sizable percentage of all deaths in old age, via stroke or heart attack when lesions rupture. Much of the focus in the medical and research communities is on cholesterol in the bloodstream as a contributing factor to the condition, but atherosclerosis should be thought of as being primarily caused by the dysfunction of the macrophage cells responsible for removing cholesterol from blood vessel tissues, handing it off to HDL particles to return to the liver. In youth these cells function just fine, and young people don’t develop lesions. In old age, however, it is a different story.

Macrophages are vulnerable to oxidized cholesterol and to the signaling of chronic inflammation. Both can degrade their ability to transport cholesterol, and they can develop into senescent foam cells that make the local environment even more inflammatory. They also die in large numbers, overwhelmed by cholesterol, and the debris of cell death expands the lesion that the macrophages should be helping to remove. It is because oxidized cholesterol is important in this process that reductions in overall cholesterol in the bloodstream can slow the progression of atherosclerosis. Treatments such as statins have become widely used as a result, but they do not lead to significant reversal of existing lesions.

Scientists here note that most of the work on atherosclerosis to date focuses on reducing LDL cholesterol in the bloodstream, which is to say cholesterol attached to an LDL particle. But other forms of cholesterol are also present in the blood stream, the so-called remnant cholesterol, and the research community has underestimated its presence and contribution to atherosclerosis. This has implications for the various approaches taken to try to control the condition, and further demonstrates that perhaps it is a better idea to focus on the macrophages rather than on the cholesterol. If macrophages can be made resilient to oxidized cholesterol, either by removing that cholesterol in a targeted way, by preventing it from being created in the first place, or by giving the macrophages additional capabilities, as we’re working on at Repair Biotechnologies, then this should go a long way towards the goal of reversal of atherosclerosis.

Levels of ‘Ugly Cholesterol’ in the Blood are Much Higher than Previously Imagined

Three quarters of the Danish population have moderately elevated levels of cholesterol. If cholesterol levels are too high, risk of cardiovascular disease is increased. Often, LDL cholesterol, the so-called bad cholesterol, is considered the culprit. However, new research shows that a completely different type of cholesterol may be more responsible than previously assumed. What we are talking about is remnant cholesterol To their surprise, the researchers have discovered that the amount of remnant cholesterol in the blood of adult Danes is much higher than previously believed. From the age of 20 until the age of 60, the amount in the blood is constantly increasing, and for many people it remains at a high level for the rest of their lives.

“Our results show that the amount of remnant cholesterol in the blood of adult Danes is just as high as the amount of the bad LDL cholesterol. We have previously shown that remnant cholesterol is at least as critical as LDL cholesterol in relation to an increased risk of myocardial infarction and stroke, and it is therefore a disturbing development.” The results are based on data from people from the Copenhagen General Population Study. A total of 9,000 individuals had cholesterol in their fat particles in the blood measured by metabolomic techniques. “Previous studies from the Copenhagen General Population Study show that overweight and obesity are the main cause of the very high amount of remnant cholesterol in the blood of adult Danes. In addition, diabetes, hereditary genes and lack of exercise play a part.”

In 2018, a large international, controlled clinical trial was published that clearly showed that when triglycerides and thus remnant cholesterol were reduced by the help of medication in people with elevated levels in the blood, the risk of cardiovascular disease was reduced by 25%. “Our findings point to the fact that prevention of myocardial infarction and stroke should not just focus on reducing the bad LDL cholesterol, but also on reducing remnant cholesterol and triglycerides. So far, both cardiologists and GPs have focused mostly on reducing LDL cholesterol, but in the future, the focus will also be on reducing triglycerides and remnant cholesterol.”

A third of nonfasting plasma cholesterol is in remnant lipoproteins: Lipoprotein subclass profiling in 9293 individuals

Increased concentrations of calculated remnant cholesterol in triglyceride-rich lipoproteins are observationally and genetically, causally associated with increased risk of ischemic heart disease; however, when measured directly, the fraction of plasma cholesterol present in remnant particles is unclear. We tested the hypothesis that a major fraction of plasma cholesterol is present in remnant lipoproteins in individuals in the general population.

We examined 9293 individuals from the Copenhagen General Population Study using nuclear magnetic resonance spectroscopy measurements of total cholesterol, free- and esterified cholesterol, triglycerides, phospholipids, and particle concentration. Fourteen subclasses of decreasing size and their lipid constituents were analysed: six subclasses were very low-density lipoprotein (VLDL), one intermediate-density lipoprotein (IDL), three low-density lipoprotein (LDL), and four subclasses were high-density lipoprotein (HDL). Remnant lipoproteins were VLDL and IDL combined.

Mean nonfasting cholesterol concentration was 72 mg/dL for remnants, 78 mg/dL for LDL, and 71 mg/dL for HDL, equivalent to remnants containing 32% of plasma total cholesterol. Of 14 lipoprotein subclasses, large LDL and IDL were the ones containing most of plasma cholesterol. The plasma concentration of remnant cholesterol was from 54 mg/dL at age 20 to 74 mg/dL at age 60. Corresponding values for LDL cholesterol were from 58 mg/dL to 81 mg/dL. Thus, using direct measurements, one third of total cholesterol in plasma was present in remnant lipoproteins, that is, in the triglyceride-rich lipoproteins IDL and VLDL.

Reviewing Progress Towards Regenerative Therapies for Age-Related Hearing Loss

Today’s open access paper is a review of present progress towards regenerative therapies that can reverse hearing loss. Progressive hearing loss is pervasive in old age, and accelerates considerable in the later stages of life. Hearing loss correlates with cognitive decline, and while it is plausible that this is because of degeneration of central nervous system function, there is also the consideration that loss of hearing isolates people and deprives them of interactions that stimulate brain activity. It is well demonstrated in mice that environment richness has a strong impact on the brain and its pace of aging.

Much of the research into age-related hearing loss is focused on the sensory hair cells of the inner ear. These detect the pressure waves of sound and in response pass impulses into nervous system connections leading to the brain. There is some evidence for loss of these cells to be the problem, and some evidence for the cells to survive in sufficient numbers, but lose their connections to the brain. Numerous research teams over the past decade or more have worked on producing regenerative therapies to regrow functional hair cells in the aged inner ear. Numerous strategies have been attempted, such as adapting mechanisms from regenerative species that can regrow hair cells as adults, or direct stimulation of pathways such as Notch that are associated with growth. Varying degrees of success have been demonstrated in mice, but as is often the case, progress towards the clinic remains frustratingly slow.

Hearing regeneration and regenerative medicine: present and future approaches

More than 5% of the world population lives with some degree of hearing impairment. The main factors behind hearing degeneration are ototoxic drugs, aging, continued exposure to excessive noise and infections. After an injury, the auditory system is damaged irreversibly, because the regeneration system is inhibited or deactivated in higher mammals, oppositely to other non-mammalian vertebrates. The pool of adult stem cells in the inner ear drops dramatically after birth. Therefore, an endogenous cellular source for regeneration is absent. In mammals, hair cells (HCs) are only generated during a short embryonic period; hence, their loss in adults produces an irreversible hearing defect. Similarly, the spiral ganglion neurons (SGNs) degeneration is unrecoverable and in the case of synaptic loss, recovery has been shown to be limited.

Because of the drastic reduction in the number of stem cells in the inner ear after the neonatal period, the autonomous regenerating capacity is almost depleted. Therefore, many research groups have focused their efforts on developing stem cell-based treatments to restore HC, SGN, and SC populations. The auditory regeneration field is mainly focus on embryonic stem cells, adult stem cells, or induced pluripotent stem cells (iPSCs). However, nowadays the main issues to be solved are the obtaining of a proper efficiency in the production of auditory stem cells and to demonstrate the utility and safety of these cells in a clinical context. Experimentation in animal models with regenerative capacity, such as zebrafish or avian models, has shown that their auditory regeneration is guided by the same genetic pathways activated during embryonic development. That mechanism leads to HC or stereocilia regeneration by different mechanisms, that have aroused great interest for the development of novel therapies that can reconstruct these pathways in humans.

In our opinion, the important discoveries in this area are mainly focused on the development of methods for stem cell transplantation, improving migration, survival, and new genetic systems for cell fate monitoring. Different routes for stem cell transplantation to the cochlea have been tested, such as through the perilymph or the endolymph. Although these techniques are promising, their results show a low cell survival rate, with only small populations of new cells at the target tissue. Transplantation of cells into the modiolus (bone lamina inside the cochlea) or in the cochlear nerve, showed a higher cell survival rate and increased migration to the target. However, the transplantation process involves potential hearing damage. The direct transplantation of stem cells on the side wall tissue of the cochlea seems to achieve efficient results. The abundance of tissue and blood supply to the area, may be responsible for the increased survival of grafted cells in the wall.

In our opinion, hearing regeneration should be considered from a multidisciplinary point of view, not only focused on stem cells, but also considering molecular mediators as a strategy to improve the outcome. Some combined therapies have been shown to be a better approach to treat some diseases than singular therapies, for instance, stem cell delivery with gene therapy to treat critical limb ischemia. The transplantation of stem cell-derived otic progenitors or adult stem cells (as neural stem cells), results in a significant improvement in hearing, which is especially noticeable in neuronal regeneration. However, the cells have to properly migrate to the damaged area and promote the establishment of functional synaptic connections between HCs and SGNs, which could be improved with molecular mediators or genetic engineering.

The Present Popularity of Epigenetic Reprogramming to Treat Aging

A fair number of research groups are presently working on ways to force large numbers of cells in the body to adopt more youthful epigenetic profiles. Much of this research is an outgrowth of the discovery of induced pluripotency, the ability to reprogram any cell into a pluripotent stem cell that is largely indistinguishable from an embryonic stem cell, capable of generating any of the cell types in the body. This process also happens to reset many of the epigenetic markers of age that are found in cells in old tissues, alongside restoring mitochondrial function by clearing out damaged mitochondria, and a few other interesting changes. The article here focuses on one representative project, but readers here might be more familiar with the work of in the same space, since it was covered recently.

The important question to be addressed here is this, since it is frequently mentioned: are epigenetic changes a cause of aging? To my eyes the answer is no, a thousand times no. They are – they must be – a downstream consequence of the true cause, which is the molecular damage that accumulates with age as a normal side-effect of the operation of cellular metabolism. However, since these epigenetic changes themselves cause further harm, one can, in principle and in animal studies, produce benefits by forcing cells to adopt a more youthful epigenetic profile for various genes of interest. But this does nothing to address the cause of aging, the underlying damage.

Without repair, the underlying causative damage of aging will continue to cause all of the problems that cannot be ameliorated by forcing a mass change in epigenetic programming and consequent cellular behavior. Consider the presence of molecular waste that the body cannot effectively clear, such as persistent cross links degrading extracellular matrix elasticity, or hardy constituents of lipofuscin making autophagy inefficient in long-lived cells, or potentially cancerous nuclear DNA damage. I predict that epigenetic reprogramming is not going to meaningfully address these line items, because youthful cells and tissues cannot meaningfully address these forms of damage if present. Reprogramming may well turn out to be as useful a tool as stem cell therapies for the purpose of regeneration of functional tissues, though with a very different focus on the type of functional improvement obtained. But be wary of those who claim that epigenetic change is the cause of aging, and that turning it back will fix all issues.

Has this scientist finally found the fountain of youth?

Izpisúa Belmonte, a shrewd and soft-spoken scientist, has access to an inconceivable power. These mice, it seems, have sipped from a fountain of youth. Izpisúa Belmonte can rejuvenate aging, dying animals. He can rewind time. But just as quickly as he blows my mind, he puts a damper on the excitement. So potent was the rejuvenating treatment used on the mice that they either died after three or four days from cell malfunction or developed tumors that killed them later.

The powerful tool that the researchers applied to the mouse is called “reprogramming.” It’s a way to reset the body’s so-called epigenetic marks: chemical switches in a cell that determine which of its genes are turned on and which are off. Erase these marks and a cell can forget if it was ever a skin or a bone cell, and revert to a much more primitive, embryonic state. The technique is frequently used by laboratories to manufacture stem cells. But Izpisúa Belmonte is in a vanguard of scientists who want to apply reprogramming to whole animals and, if they can control it precisely, to human bodies.

Izpisúa Belmonte believes epigenetic reprogramming may prove to be an “elixir of life” that will extend human life span significantly. Life expectancy has increased more than twofold in the developed world over the past two centuries. Thanks to childhood vaccines, seat belts, and so on, more people than ever reach natural old age. But there is a limit to how long anyone lives, which Izpisúa Belmonte says is because our bodies wear down through inevitable decay and deterioration. “Aging is nothing other than molecular aberrations that occur at the cellular level.” It is, he says, a war with entropy that no individual has ever won.

The treatment Izpisúa Belmonte gave his mice is based on a Nobel-winning discovery by the Japanese stem-cell scientist Shinya Yamanaka. Starting in 2006, Yamanaka demonstrated how adding just four proteins to human adult cells could reprogram them so that they look and act like those in a newly formed embryo. To many scientists, Yamanaka’s discovery was promising mainly as a way to manufacture replacement tissue for use in new types of transplant treatments. Researchers at the Spanish National Cancer Research Centre took the technology in a new direction when they studied mice whose genomes harbored extra copies of the Yamanaka factors. Turning these on, they demonstrated that cell reprogramming could actually occur inside an adult animal body, not only in a laboratory dish. The experiment suggested an entirely new form of medicine. You could potentially rejuvenate a person’s entire body. But it also underscored the dangers. Clear away too many of the methylation marks and other footprints of the epigenome and “your cells basically lose their identity.”

To others, however, the evidence for rejuvenation is plainly in its infancy. Jan Vijg, chair of the genetics department at the Albert Einstein College of Medicine in New York City, says aging consists of “hundreds of different processes” to which simple solutions are unlikely. Theoretically, he believes, science can “create processes that are so powerful they could override all of the other ones. We don’t know that right now.” An even broader doubt is whether the epigenetic changes that Izpisúa Belmonte is reversing in his lab are really the cause of aging or just a sign of it – the equivalent of wrinkles in aging skin. If so, Izpisúa Belmonte’s treatment might be like smoothing out wrinkles, a purely cosmetic effect. “We have no way of knowing, and there is really no evidence, that says the DNA methylation is causing these cells to age,” says John Greally, another professor at Einstein. The notion that “if I change those DNA methylations, I will be influencing aging has red flags all over it.”

An Interview with Daniel Ives of Shift Bioscience

Shift Bioscience is working on a way to improve mitochondrial function in old tissues. Mitochondria, as you might recall, are the power plants of the cell, responsible for producing chemical energy store molecules used to power cellular processes. Every cell has a herd of hundreds of mitochondria that replicate like bacteria and are culled when damaged by the quality control process of mitophagy. Mitochondrial function nonetheless declines with age, and this affects all cell activities. It is particularly relevant to age-related disease in energy hungry tissues such as the brain and muscles, but the detrimental effects are global throughout the body.

Aging degrades mitochondrial function via several mechanisms, and an important one is the loss of quality control, allowing broken mitochondria to overtake cells. Systematically removing those broken mitochondria on a consistent, ongoing basis should be beneficial, but the question has always been how to manage this feat. The present Shift Bioscience candidate small molecule drug enables functional, undamaged mitochondria to better outcompete their damaged peers for the limited supply of proteins needed to function. This can in principle tip the balance back towards healthy rather than dysfunctional mitochondria in a tissue.

You are proposing to search for small molecules that could potentially slow down progression of the epigenetic clock. Can you tell us a little bit more about your drug screening process?

It is very difficult to implement high-throughput drug screening for biological aging, since contemporary assays of biological age are cell based and can take months to complete. This would require millions of cell lines to be maintained in parallel for months, and this is simply too cost prohibitive. To overcome this challenge, we plan to utilize an approach called ‘protein interference’, where a library of protein fragments is delivered by virus to a population of cells containing a biological age-reporter. Each cell receives a unique protein fragment that may bind to any protein at any position, and through this binding, we could discover peptides that slow down, stop, or reverse biological aging. These protein fragments could be used as therapeutics or guide the design of small molecules.

Many of the hallmarks of aging influence the epigenetic aging clocks; what makes you consider the mitochondria the optimal target for therapeutic interventions?

The discovery of epigenetic aging clocks had particular significance to our company, as they provided the opportunity to audit our key hypothesis (e.g. mitochondrial dysfunction is an important part of aging). To do this, we measured the clock in human cells without a functional citric acid cycle, which severely reduces energy production by mitochondria. This caused a 16-year acceleration of the clock compared to control cells, which, to our knowledge, is the largest acceleration reported.

So far you claim to have identified one family of small molecules that appear to slow the epigenetic clock by at least 50% by restoring mitochondrial function in aged cells. Does this mean that the mitochondria are being repaired or replaced?

In mice, we have preliminary data indicating a deceleration of biological aging by 40% in the brain and 60% in the heart due to the small molecules (as defined by the epigenetic clock). Current evidence suggests that under such conditions, functional mitochondria are able to ‘outbreed’ dysfunctional mitochondria and become the dominant population. This is an example of overcoming damage by dilution, in contrast to conventional repair.

Cells have the unfortunate habit of favoring mutated mitochondria over healthy ones, and these damaged mitochondria can take over a cell in a relatively short time. How might we prevent the cells from making this poor choice so that they retain their healthy mitochondria?

Though our small molecule approach is closest to clinical development, there are other exciting approaches to combating mutated mitochondria in development. Aubrey de Grey has proposed transferring the mitochondrial DNA to the safety of the nucleus, an approach called ‘allotopic expression’. This is not as far-fetched as it might seem, since evolution has already encouraged the vast majority of mitochondrial DNA to transfer to the relative safety of the nucleus. Why not finish off the job that evolution started? The second approach is to deliver endonucleases to mitochondria that specifically target and digest mutated mitochondrial DNA. Researchers have recently validated this approach in mouse models of mitochondrial disease.

So where are you now in terms of development of a therapy and potential human trials?

We are currently creating an enhanced molecule that overcomes some of the limitations of this small molecule family (e.g. they are quickly cleared out of the bloodstream). Once validated in cellular and animal models, we plan to target rare inherited mitochondrial diseases with this enhanced molecule because they provide the fastest route to the clinic.

The Gut Microbiome Changes Over the Course of Aging

This short open access review is a good introduction to what is known of the changes to the microbial population of the gut that take place over the course of aging. Collectively, the activity of gut microbes is influential on health, arguably to a similar degree as exercise, though far less well quantified at this time. Altering the distribution of bacterial populations in older animals, to better resemble what is observed in young animals, leads to benefits to health, for example. Some of the specific mechanisms by which beneficial gut microbes improve health are being uncovered, such as the secretion of propionate, a compound now being developed as a dietary supplement. Much more remains to be established, of course; this is a part of the broader field still in its comparative infancy.

Dwelling at the interface between host epithelia and the external environment, commensal microbes actively modulate development, nutrient absorption, and disease onset in the host. Host metabolism is significantly modulated by commensal microbes, and the gut microbial composition significantly affects blood metabolite composition. Just as the composition of the microbiota varies within and between tissues, microbial consortia do also vary through time within individual tissues. Although individual gut microbiota are largely unstable in the first years of life, they become more stable during adulthood and undergo dramatic changes in richness and composition upon onset of disease and frailty. The onset of specific diseases, such as cancer, obesity, diabetes, or inflammatory bowel disease, is associated with specific microbial signatures.

Studies in humans and laboratory model organisms, such as flies, fish, and mice, have additionally shown that the composition of the gut microbiota dramatically changes during aging and is associated with host health and life span. In mice, e.g., lipopolysaccharide (LPS) from gut microbiota can accelerate age-dependent inflammation (“inflammaging”), and mice lacking Toll-Like receptor 4 (TLR4), which is the LPS receptor, are protected from age-dependent inflammation, showing that a microbial-specific substrate induces aging-specific phenotypes. Inflammaging can be further exacerbated in germ-free mice by gut microbiota transfers from aged donor mice, showing a direct causal relation between age-specific microbial communities and host aging.

Using deep learning to analyze human microbiome data helped build a human microbiome aging clock, which predicts host age with an accuracy of about four years. While during adulthood microbial composition contributes to cellular and tissue homeostasis, age-dependent changes in the microbial composition may contribute to increasing frailty and disease onset in later life. The causes leading to the changes in microbiota composition and function during host aging are still poorly understood and possibly include direct or indirect microbial selection by the host and microbe-microbe interactions, as well as microbial evolution.

MicroRNA miR-122 is Important in Improved Mitochondrial Function Resulting from Calorie Restriction

Calorie restriction improves near all measures of metabolic health, mitochondrial function included. Mitochondria are the power plants of the cell, and they accumulate damage and dysfunction with age, in part because the processes of quality control intended to remove worn and broken mitochondria falter. Calorie restriction improves the situation, but, characteristically, does so in a very broad way that makes it challenging to pick out the important mechanisms from the many other sweeping changes in cellular activity. Researchers here suggest that upregulation of miR-122 is noteworthy, but it is just one of many changes noted in the paper.

Both caloric restriction (CR) and mitochondrial proteostasis are linked to longevity, but how CR maintains mitochondrial proteostasis in mammals remains elusive. MicroRNAs (miRNAs) are well known for gene silencing in cytoplasm and have recently been identified in mitochondria, but knowledge regarding their influence on mitochondrial function is limited.

Here, we report that CR increases miRNAs, which are required for the CR-induced activation of mitochondrial translation, in mouse liver. The ablation of miR-122, the most abundant miRNA induced by CR, or the retardation of miRNA biogenesis via Drosha knockdown significantly reduces the CR-induced activation of mitochondrial translation. Importantly, CR-induced miRNAs cause the overproduction of mitochondrial DNA encoded proteins, which induces the mitochondrial unfolded protein response (UPRmt), and consequently improves mitochondrial proteostasis and function.

These findings establish a physiological role of miRNA-enhanced mitochondrial function during CR and reveal miRNAs as critical mediators of CR in inducing UPRmt to improve mitochondrial proteostasis.

Increasing NAD+ to Improve Mitochondrial Function Slows Age-Related Hearing Loss in Mice

There is a great deal of hype surrounding the use of compounds that increase NAD+ levels in mitochondria, thereby improving the function of old tissue. This doesn’t address the underlying molecular damage that leads to reduced NAD+ levels in later life, and thus might be thought of as something akin to pressing the accelerator harder in a car with a worn engine, but there is a slow accumulation of evidence for some degree of benefit to result. For example, reduced blood pressure in older hypertensive individuals, suggesting improved function of smooth muscle tissue in blood vessel walls. The example today is quite different, as the focus is on the function of cochlear tissue of the inner ear that is vital to hearing, and which suffers the loss of cells and cell function with age.

Age-related hearing loss (ARHL) or presbycusis is the most common cause of hearing loss and sensory disability, characterized by gradual deterioration of auditory sensitivity at all frequencies, with increasing age. ARHL still remains largely untreated. Despite the fact that the mechanism of ARHL has remained elusive, multiple studies have demonstrated that age-dependent oxidative stress, reactive oxygen species (ROS) metabolism, up-regulation of inflammatory responses, and mitochondrial dysfunction in parallel with cellular signaling and gene expression changes are implicated in this process. Particularly, structural changes and degeneration of inner ear cells, such as sensory hair cells, spiral ganglion neurons, and stria vascularis, are characteristics of aged mammals.

NAD+ and NADH are crucial mediators of energy metabolism and cellular homeostasis, as they act as cofactors for NAD+-dependent enzymes, including sirtuins (SIRTs), histones, and poly (ADP-ribose) polymerases (PARPs). Notably, cytosolic-free NAD+ levels decrease under various pathological conditions, including aging. There is strong evidence to support a role for SIRT1 in the process of aging and cell death, through deacetylation of targets such as NF-κB and p53. In addition, it has been proven that SIRT3 plays key roles in mitochondrial functions through deacetylation of mitochondrial proteins. Therefore, we hypothesize that long-term induction of high cellular NAD+ levels may produce protective effects against ARHL.

We investigated the effect of β-lapachone (β-lap), a known plant-derived metabolite that modulates cellular NAD+, on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD+ during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro-inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF-κB, p53, and IDH2. However, augmentation of NAD+ by β-lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD+ levels by pharmacological agents may be a tangible therapeutic option for treating various age-related diseases, including ARHL.

Comparing the Metabolomic Signature of Aging in Mice and Naked Mole-Rats

Naked mole-rats live something like ten times longer than similarly sized mice, show few signs of aging until very late life, and are near immune to cancer. These two species are used as models by researchers to try to understand how, in detail, differences in metabolism can lead to the observed large differences in life span across mammalian species. Since metabolism is ferociously complex, this is very much a work in progress; in the grand scheme of things, only small inroads and starting points have been established. I fully expect investigations of the detailed interactions of metabolism and aging to be ongoing and nowhere near complete thirty years from now, when rejuvenation therapies based on repair of the well-known root causes of aging are a going concern. While it is of course the right thing to do to attempt to fully understand metabolism, this work is not the fast path to new medical technologies that will have significant impacts on human health and longevity.

Although biological and chronological time can be dissociated to some extent by experimental manipulation, aging appears to be the most important risk factor for the deterioration of normal physiological functions. One species that – to a certain degree – escapes from the rule that natural life expectancy declines with body mass is the naked mole-rat (Heterocephalus glaber). Although this rodent has a similar size as the laboratory mouse (Mus musculus), it lives 10-20 times longer without showing any visible signs of aging. Furthermore, the naked mole-rat can live for over 32 years in captivity, without facing any increased age-related risk of mortality, challenging Gompertz’s mortality law, and thus establishing the naked mole-rat as a non-aging mammal.

Not only naked mole-rats can live an extremely long life, but they also show a remarkably long healthspan associated with almost no decline in physiological or biochemical functions for more than 20 years. For example, cardiac functions are well preserved in aged naked mole-rats, cognitive functions do not decline with age and the naked mole-rat brain seems to be naturally protected from neurodegenerative processes, and also very little pathologic alterations have been found in the kidneys of aged naked mole-rats. In addition, typical signs of aging, such as loss of fertility, muscle atrophy, bone loss, changes in body composition or metabolism are mostly absent in the naked mole-rats. Finally, the incidence of age-related diseases such as cancers or metabolic disorders is extremely low in the naked mole-rat.

We used mass spectrometric metabolomics to analyze circulating plasma metabolites in both species at different ages. Interspecies differences were much more pronounced than age-associated alterations in the metabolome. Such interspecies divergences were found to affect multiple metabolic pathways that involve amino, bile, and fatty acids as well as monosaccharides and nucleotides.

The most intriguing metabolites were those that had previously been linked to pro-health and antiaging effects in mice and that were significantly increased in the long-lived rodent compared to its short-lived counterpart. This pattern applies to α-tocopherol and polyamines (in particular cadaverine, N8-acetylspermidine and N1,N8-diacetylspermidine), all of which were more abundant in naked mole-rats than in mice. Moreover, the age-associated decline in spermidine and N1-acetylspermidine levels observed in mice did not occur, or is even reversed (in the case of N1-acetylspermidine) in naked mole-rats. In short, the present metabolomics analysis provides a series of testable hypotheses to explain the exceptional longevity of naked mole-rats.

The Inflammatory Feedback Loop Produced by Senescent Cells in the Aging Heart

Senescent cells are an important cause of degenerative aging. Lingering senescent cells accumulate over time and disrupt tissue function and immune function via their secretions. An insidious part of this is that the signals secreted by senescent cells cause other nearby cells to be more likely to become senescent. Thus once they start to accumulate the result is an accelerating feedback loop of dysfunction and degeneration. There are many such feedback loops in aging, which is why the process starts slow and then speeds up considerably in later life.

Aging is a major risk factor in the development of chronic diseases, especially cardiovascular diseases. Age-related organ dysfunction is strongly associated with the accumulation of senescent cells. Cardiac mesenchymal stromal cells (cMSCs), deemed part of the microenvironment, modulate cardiac homeostasis through their vascular differentiation potential and paracrine activity. Transcriptomic analysis of cMSCs identified age-dependent biological pathways regulating immune responses and angiogenesis. Aged cMSCs displayed a senescence program characterized by Cdkn2a expression, decreased proliferation and clonogenicity, and acquisition of a senescence-associated secretory phenotype (SASP).

Increased CCR2-dependent monocyte recruitment by aged cMSCs was associated with increased IL-1ß production by inflammatory macrophages in the aging heart. In turn, IL-1ß induced senescence in cMSCs and mimicked age-related phenotypic changes such as decreased CD90 expression. The CD90+ and CD90- cMSC subsets had biased vascular differentiation potentials, and CD90+ cMSCs were more prone to acquire markers of the endothelial lineage with aging. These features were related to the emergence of a new cMSC subset in the aging heart, expressing CD31 and endothelial genes.

These results demonstrate that cMSC senescence and SASP production are supported by the installation of an inflammatory amplification loop, which could sustain cMSC senescence and interfere with their vascular differentiation potentials.

DGCR8 Overexpression Attenuates the Accumulation of Senescent Cells with Age

Given the newfound acceptance of cellular senescence as an important cause of aging, many more research groups are assessing the impact of senescent cells in their research into aging. Here, the focus is on chromatin organization, a collection of nuclear structures and processes in the cell that appear to have some influence over the pace of aging over a lifetime. The researchers discover that the gene DGCR8 accelerates the appearance of senescent cells and dysfunction when mutated, and thus producing broken protein machinery, but slows the accumulation of lingering senescent cells when overexpressed in its correct form. This touches on some of the same machinery of the cell as the mir-122 findings discussed a few days ago, and that work is worth comparing with the notes here, as an example of just how complicated this all is.

Stem cell aging is newly recognized as an important culprit in organismal aging. For example, aging of mesenchymal stem cells (MSCs) has been shown to drive aging-associated tissue degeneration. MSCs, which have the potential to differentiate into mesodermal lineages like osteoblasts, chondrocytes, and adipocytes, can be isolated from various tissues including bone marrow, cord blood, adipose tissue, and dental pulp. Premature depletion of MSCs is observed in patients with Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS), two premature aging diseases that are associated with accelerated atherosclerosis, osteoporosis, and osteoarthritis. Despite numerous studies showing that MSCs play pivotal roles in tissue rejuvenation, regeneration, and repair by differentiating into various somatic cell types, little is known about the key regulators of MSC aging.

Aging-associated declines in stem cell functionality are often accompanied by epigenetic changes, such as changes in genomic DNA methylation, histone modifications, and chromatin remodeling enzymes. Heterochromatin domains are structurally inaccessible and usually transcriptionally inactive. These domains are established during early stages of embryogenesis and are gradually lost with aging, resulting in the de-repression of normally silenced genes. Whereas heterochromatin loss drives human MSC (hMSC) aging, the re-establishment of heterochromatin alleviates premature aging and promotes longevity in Drosophila and human cells, suggesting that the maintenance of heterochromatin organization could be an effective therapeutic intervention against aging.

DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. A truncated version of DGCR8 accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its microRNA-processing activity. Further studies revealed that DGCR8 maintained heterochromatin organization. DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and mouse osteoarthritis. Taken together, these analyses uncovered a novel, microRNA processing-independent role in maintaining heterochromatin organization and attenuating cellular senescence by DGCR8, thus representing a new therapeutic target for alleviating human aging-related disorders.

Cytomegalovirus in the Immunology of Aging

The open access editorial noted here serves as an introduction to some of the current thinking on the role of cytomegalovirus (CMV) in the age-related decline of the immune system. CMV infection is pervasive throughout the population, particularly in the old. This persistent viral infection cannot be effectively cleared by the immune system, and an ever greater percentage of immune cells become uselessly specialized to fight CMV. This leaves ever fewer immune cells ready to tackle other threats. This seems an important component of immune dysfunction, one that can perhaps be addressed by selectively destroying these immune cells to free up space for replacements. The research community is by no means unified on this view of CMV, however, as illustrated here.

Aging represents a paradox of immunodeficiency and inflammation (inflammaging) and autoimmunity. Over the lifespan there are changes in the architecture and functioning of the immune system, often termed immunosenescence. Recently, there have been major developments in understanding the cellular and molecular bases, and genetic and epigenetic changes, in the innate and the adaptive immune system during aging, and the interactions between these separate arms of vertebrate immunity. Limited longitudinal studies have begun to reveal biomarkers of immune aging, which may be considered to constitute an “immune risk profile” (IRP) predicting mortality and frailty in the very elderly. Hallmark parameters of the IRP may also be associated with poorer responses to vaccination.

The usually asymptomatic infection with the widespread persistent cytomegalovirus, CMV, has an enormous impact on immune biomarkers, but according to the circumstances and depending on what is measured, this can translate into a detrimental or a beneficial effect. The prevalence of CMV infection in populations in industrialized countries increases with age, and within individuals the degree of immune commitment to anti-CMV responses also increases with age. This may cause pathology by maintaining higher systemic levels of inflammatory mediators (“inflammaging”) and decreasing the “immunological space” available for immune cells with other specificities, or it may exert beneficial “adjuvant-like” effects. Modalities to prevent or reverse immunosenescence may therefore need to include targeting infectious agents such as CMV in a robustly personalized manner.

Because of the increasing recognition that CMV has a marked impact on immune parameters commonly associated with age, it is crucial to dissect out whether age or CMV is responsible for altering biomarkers predictive of health status (e.g., frailty) or other important parameters such as response to vaccination (especially seasonal influenza). Researchers have investigated whether T cell responsiveness to a range of CMV proteins is different in younger and older healthy people and whether relaxation of anti-CMV immunosurveillance in later life could contribute to disease. They found that CMV-specific CD4+ T cells secreting the anti-inflammatory cytokine IL 10 were predominantly directed to latency-associated CMV proteins and that these responses were not greater in the elderly than the young. However, the frequency of IFN-γ-secreting CD4+ T cells correlated with latent viral genome copy number in monocytes. They conclude that viremia is rare in the elderly due to the maintenance of T cell responsiveness but that CMV can be an important comorbidity factor in people who are not perfectly healthy.

Further complications in analyzing the impact of CMV may arise because most human data are derived from studies using peripheral blood. However, the bone marrow harbors large amounts of late-stage differentiated CD8 T cells possibly because the production of IL 15 is greater in CMV-infected individuals. Also, expression of the NK-associated receptor CD161 is similar in CMV-seropositive and seronegative young subjects but is different in the elderly, illustrating that CMV effects may be different at different ages. The large accumulations of CMV-specific T cells, also in the bone marrow, may contribute to the state of inflammaging, but it is likely that other immune (and non-immune) cells are also major contributors. Cells of the innate immune system far outnumber those of adaptive immunity and may also be heavily influenced by the presence of CMV, contributing to inflammaging.

Even Low Levels of Infection Can Cause Cardiac Dysfunction in Older Individuals

Researchers here suggest that infection plays an important role in cardiovascular disease in later life, and that the chronic inflammation of aging is a factor in allowing infection to cause significant harm to the heart. This is one of countless issues that could be mitigated through rejuvenation of the aging immune system, fixing the underlying issues that cause the immune system to become less functional and more inflammatory. These include atrophy of the thymus, the loss of thymic tissue where T cells of the adaptive immune system mature, loss of hematopoietic stem cell capacity, leading to reduced generation of new immune cells, the structural aging of lymph nodes, preventing immune cells from efficiently coordinating with one another, and the accumulation of senescent and otherwise dysfunctional immune cells.

Infection and infectious disease associated pathologies are often complicated by delays in immune response generation and excess inflammation that impact infection resolution. The term “inflammaging” was coined to denote the multifaceted dysregulation of homeostatic processes that over time culminates in quantifiable, organism-wide shifts towards inflammation in old age. As we shift our focus towards understanding the impact of inflammaging, we have recently determined that inflammaging may also accelerate the decline in cardiovascular fitness.

Age is a major prognostic factor for the development of non-tuberculous mycobacteria (NTM) disease, with recent clinical data reflecting increased incidence of NTM infection in elderly individuals. It is also known that tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) can cause pericarditis, endocarditis, and myocarditis leading to sudden deaths. TB is a major global killer and it is estimated that 57% of all TB deaths globally occur in individuals older than 65. Based upon abundant circumstantial evidence, a direct link between mycobacterial infections, aging, and cardiac dysfunction was hypothesized by our group.

We examined how mycobacterial infection and inflammaging catalyze the decline in cardiovascular function in the elderly. Young (3 months) and old (18 month) female C57BL/6 mice were infected with a sub-lethal dose of Mycobacterium avium (M. avium), an NTM. We observed no differences in the M. avium bacterial numbers in the lung, liver, or spleen between young and old M. avium infected mice. However, through the course of M. avium infection, old mice developed severe dysrhythmia and developed pericarditis. Moreover, the hearts of M. avium infected old mice had increased cardiac hypertrophy, fibrosis, expression of pro-inflammatory genes, and infiltration of immune cells, which are hallmarks of myocarditis.

Since these cardiac abnormalities only manifested in old mice, we investigated several factors that contribute to this form of age dependent infectious myocarditis. Independent of M. avium infection, old mice had increased levels of pro-inflammatory cytokines in their serum, which may have predisposed old mice to infectious myocarditis. The reasons for increased inflammation in old age are multifaceted, and future studies will be needed to identify the principal sources of increased inflammation and whether ameliorating inflammation prevents NTM associated cardiac complications in old mice. This highlights how even low or what we may generally consider as insignificant bacterial loads can profoundly impact cardiovascular health.

A Comparatively Simple Approach to Improve Engraftment of Transplanted Cells

The issue with first generation cell therapies for regenerative medicine is that transplanted cells near entirely fail to engraft into tissue. There are exceptions, but for the most part, the cells used in therapy die rather than take up productive work to enhance tissue function. Where benefits occur, they are mediated by the signals secreted by the transplanted cells in the brief period they remain alive. Mesenchymal stem cell therapies that reduce chronic inflammation for some period of time are an example of the type. They are good at that outcome of reduced inflammation, but highly unreliable when it comes to any other desired result, such as increased regeneration.

Thus an important goal in regenerative medicine and tissue engineering circles is to solve the issue of engraftment, and enable the reliable delivery of cells that survive to participate in improving tissue function. Numerous strategies have been tried, with varying degrees of success. The best to date is to provide cells with a surrounding biodegradable scaffold that incorporates supporting nutrients and signals. This can work quite well when cells are allowed to form a pseudo-normal tissue like structure prior to transplantation, for example in heart patches or retina patches. The research noted here offers quite a different and much simpler strategy to improve engraftment rates, the removal of lower quality cells from the cell population created for transplantation.

Biomedical engineers believe they can aid the failing heart by using pluripotent stem cells to grow heart muscle cells outside of the body, and then injecting those muscle cells or adding a patch made from those cells, at or near the site of the dead heart tissue. Experimental and clinical trial evidence with this approach has shown moderate improvement of the pumping ability of the heart’s left ventricle. However, the ability of the delivered cells to remuscularize the heart and improve cardiac function depends on the quality of those cells. A challenge has been low rates of engraftment by the transplanted cells.

Researchers now report a simple method to improve the quality of the delivered cells, and they found that this method – tested in a mouse heart attack model – doubled the engraftment rate of the injected stem cell-derived cardiomyocytes. The robust approach to select functionally competent, intact-DNA cells from a heterogeneous population can be easily adopted in clinical settings to yield cells that are better able to repopulate the ischemic myocardium and improve the performance of a failing heart.

Cardiac cell transplantation requires millions of stem cells or their differentiated derivatives. Cell propagation under accelerated growth conditions is a common way to get these large numbers of cells; but accelerated growth causes culture stress, including lethal DNA damage. These DNA-damaged cells are not suitable for cell transplantation and have to be removed from cell preparations. The researchers found they could activate transcription factor p53 in induced pluripotent stem cells to selectively induce programmed cell death, or apoptosis, specifically in DNA-damaged cells, while sparing DNA damage-free cells. They used Nutlin-3a, an MDM2 inhibitor, to activate the p53. After Nutlin-3a treatment, the dead cells were washed from the culture, and the remaining DNA damage-free cells were cultured normally and differentiated into cardiomyocytes.

The researchers then injected 900,000 of the derived cardiomyocytes into the border zone in the left ventricle of the mouse heart attack model. Four weeks later, the researchers found a significantly higher engraftment rate, about 14 percent, in hearts that received the DNA damage-free cardiomyocytes. Engraftment of the control derived cardiomyocytes was about 7 percent. “As this is a small molecule based approach to select DNA damage-free cells, it can be applied to any type of stem cells, though selection conditions would need to be optimized and evaluated. Other stem cell approaches for diseases such as neurodegenerative diseases, brain and spinal cord injuries, and diabetes might benefit by adopting our method.”

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The Present Popularity of Epigenetic Reprogramming to Treat Aging

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A fair number of research groups are presently working on ways to force large numbers of cells in the body to adopt more youthful epigenetic profiles. Much of this research is an outgrowth of the discovery of induced pluripotency, the ability to reprogram any cell into a pluripotent stem cell that is largely indistinguishable from an embryonic stem cell, capable of generating any of the cell types in the body. This process also happens to reset many of the epigenetic markers of age that are found in cells in old tissues, alongside restoring mitochondrial function by clearing out damaged mitochondria, and a few other interesting changes. The article here focuses on one representative project, but readers here might be more familiar with the work of in the same space, since it was covered recently.

The important question to be addressed here is this, since it is frequently mentioned: are epigenetic changes a cause of aging? To my eyes the answer is no, a thousand times no. They are – they must be – a downstream consequence of the true cause, which is the molecular damage that accumulates with age as a normal side-effect of the operation of cellular metabolism. However, since these epigenetic changes themselves cause further harm, one can, in principle and in animal studies, produce benefits by forcing cells to adopt a more youthful epigenetic profile for various genes of interest. But this does nothing to address the cause of aging, the underlying damage.

Without repair, the underlying causative damage of aging will continue to cause all of the problems that cannot be ameliorated by forcing a mass change in epigenetic programming and consequent cellular behavior. Consider the presence of molecular waste that the body cannot effectively clear, such as persistent cross links degrading extracellular matrix elasticity, or hardy constituents of lipofuscin making autophagy inefficient in long-lived cells, or potentially cancerous nuclear DNA damage. I predict that epigenetic reprogramming is not going to meaningfully address these line items, because youthful cells and tissues cannot meaningfully address these forms of damage if present. Reprogramming may well turn out to be as useful a tool as stem cell therapies for the purpose of regeneration of functional tissues, though with a very different focus on the type of functional improvement obtained. But be wary of those who claim that epigenetic change is the cause of aging, and that turning it back will fix all issues.

Has this scientist finally found the fountain of youth?

Izpisúa Belmonte, a shrewd and soft-spoken scientist, has access to an inconceivable power. These mice, it seems, have sipped from a fountain of youth. Izpisúa Belmonte can rejuvenate aging, dying animals. He can rewind time. But just as quickly as he blows my mind, he puts a damper on the excitement. So potent was the rejuvenating treatment used on the mice that they either died after three or four days from cell malfunction or developed tumors that killed them later.

The powerful tool that the researchers applied to the mouse is called “reprogramming.” It’s a way to reset the body’s so-called epigenetic marks: chemical switches in a cell that determine which of its genes are turned on and which are off. Erase these marks and a cell can forget if it was ever a skin or a bone cell, and revert to a much more primitive, embryonic state. The technique is frequently used by laboratories to manufacture stem cells. But Izpisúa Belmonte is in a vanguard of scientists who want to apply reprogramming to whole animals and, if they can control it precisely, to human bodies.

Izpisúa Belmonte believes epigenetic reprogramming may prove to be an “elixir of life” that will extend human life span significantly. Life expectancy has increased more than twofold in the developed world over the past two centuries. Thanks to childhood vaccines, seat belts, and so on, more people than ever reach natural old age. But there is a limit to how long anyone lives, which Izpisúa Belmonte says is because our bodies wear down through inevitable decay and deterioration. “Aging is nothing other than molecular aberrations that occur at the cellular level.” It is, he says, a war with entropy that no individual has ever won.

The treatment Izpisúa Belmonte gave his mice is based on a Nobel-winning discovery by the Japanese stem-cell scientist Shinya Yamanaka. Starting in 2006, Yamanaka demonstrated how adding just four proteins to human adult cells could reprogram them so that they look and act like those in a newly formed embryo. To many scientists, Yamanaka’s discovery was promising mainly as a way to manufacture replacement tissue for use in new types of transplant treatments. Researchers at the Spanish National Cancer Research Centre took the technology in a new direction when they studied mice whose genomes harbored extra copies of the Yamanaka factors. Turning these on, they demonstrated that cell reprogramming could actually occur inside an adult animal body, not only in a laboratory dish. The experiment suggested an entirely new form of medicine. You could potentially rejuvenate a person’s entire body. But it also underscored the dangers. Clear away too many of the methylation marks and other footprints of the epigenome and “your cells basically lose their identity.”

To others, however, the evidence for rejuvenation is plainly in its infancy. Jan Vijg, chair of the genetics department at the Albert Einstein College of Medicine in New York City, says aging consists of “hundreds of different processes” to which simple solutions are unlikely. Theoretically, he believes, science can “create processes that are so powerful they could override all of the other ones. We don’t know that right now.” An even broader doubt is whether the epigenetic changes that Izpisúa Belmonte is reversing in his lab are really the cause of aging or just a sign of it – the equivalent of wrinkles in aging skin. If so, Izpisúa Belmonte’s treatment might be like smoothing out wrinkles, a purely cosmetic effect. “We have no way of knowing, and there is really no evidence, that says the DNA methylation is causing these cells to age,” says John Greally, another professor at Einstein. The notion that “if I change those DNA methylations, I will be influencing aging has red flags all over it.”

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