Talking Up the Potential of the Longevity Industry

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One of the Juvenescence founders is here enthusiastic about the potential for treating aging as a medical condition. While one should always filter the remarks of people who run companies via a cynical view of their incentives, as talking up the company, the industry, and the prospects is very much expected, it is in fact the case that the longevity industry as a whole has tremendous potential. It will up-end the whole of healthcare, all expectations of what it means to be older, and will most likely become the largest industry on the planet. It will alleviate more suffering, pain, and death than any other human endeavor to date, by a very large margin.

Exactly which of the specific projects and companies will turn out to produce the lion’s share of the benefits is hard to predict in advance. That said, I am of course willing to argue that following the SENS methodology of repairing underlying damage is going to be far more effective, on balance, than interventions that target downstream metabolic states or processes. Thus of the present set of approaches, senolytic therapies to clear senescent cells seem far more likely to change the world significantly than is the case for, say, mTOR inhibitors that mimic some of the effects of calorie restriction.


Earlier this year, an executive from Juvenescence-backed AgeX predicted the field of longevity will eventually “dwarf the dotcom boom.” Greg Bailey, the UK-based anti-aging biotech’s CEO, certainly hopes so. The business of anti-aging is gaining steam – Bank of America has forecast the market will balloon to $610 billion by 2025, from an estimated $110 billion currently – but investors are cautious.

“I think there’s a huge amount of skepticism. There’s an enormous number of charlatans … I understand why they would be thinking you know, is this real? Walk into your local drugstore, you’re going to see about 50 products that claim to be anti-aging, and I can assure you that none of them are.” Bailey suggested that investors are not quite as enthusiastic about placing bets on anti-aging, as they are in the tech world. “Institutions tend to move in lockstep when they’re investing. VCs are astonishing, you know, if one of them buys the yellow halter top, all of them have to buy a yellow halter top. We’re dramatically underserved. It’s not getting the exposure that tech gets, considering the size of the market. There is a disconnect on what investors – sophisticated investors – institutions, how they’re viewing this, I don’t think they quite grasp how fast this is going to happen, and how big it’s going to be.”

Juvenescence has now raised $165 million in the last 18 months – in January it unveiled the first $46 million tranche of the Series B – and the money is being used to fund longevity projects with the lofty goal of extending human lifespans to 150 years. It is a popular vision. Inspired by Juvenescence, venture capitalist Sergey Young – who is in charge of all things longevity at the non-profit XPRIZE and VC fund BOLD Capital Partnersunveiled a $100 million fund with the same goal in February. Google-owned stealthy biotech Calico is after the same prize – and has partnered with AbbVie.

Juvenescence has been busy, collaborating with different groups and setting up joint ventures, such as Alex Zhavoronkov’s AI shop at Insilico Medicine – and has invested in firms including AgeX and LyGenesis. In February, Juvenescence debuted an anti-aging joint venture with the Buck Institute dedicated to inducing ketosis. In recent months, it spawned a new biotech called Souvien Therapeutics, which is developing medicines to address the epigenetic underpinnings of neurodegenerative diseases, and injected $6.5 million in equity financing into a preclinical metabolic disease biotech dubbed BYOMass. Juvenescence will maintain a focus on regeneration. “I’m mindful that if you live to 150, you know, people don’t want to be all wrinkled, and in a wheelchair. So what we want to be able to do is regenerate tissues.”

Link: https://endpts.com/healthier-longer-lifespans-will-be-a-reality-sooner-than-you-think-juvenescence-promises-as-it-closes-100m-round/

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The Decline of Autophagy in Skin Aging

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The maintenance processes of autophagy recycle damaged structures and protein machinery in the cell. Autophagy is influential on the course of aging, as illustrated by the fact that many of the interventions capable of slowing aging in animal models involve increased autophagic activity. Some, like calorie restriction, have been demonstrated to require autophagy in order to extend healthy life span. Further, autophagy declines with age, and this is associated with the progression of a range of age-related diseases. Better maintenance of cells means better function of tissue and a slower onset of age-related dysfunction. The research community spends a great deal of time and effort in the investigation of autophagy and how to adjust its operation, but for all that, comparatively little concrete progress has been made towards clinical therapies that upregulate autophagy in humans.


Changes of the skin belong to the most recognizable signs of aging. Accordingly, skin aging is a major area of interest for cosmetic and skin care industries. From the medical viewpoint, aging of the skin is associated with health problems including increased skin fragility, delayed wound healing, and the increased occurrence of skin cancers, the most abundant types of malignancies in humans. For a long time it has been recognized that the rate of skin aging is determined by intrinsic and extrinsic drivers, but only recent advances in skin gerontology have helped to dissect the molecular and cellular processes that underlie the aging of the skin.

Several of the aging processes are triggered or enhanced by the presence of damaged molecules and organelles within cells, and their turnover is controlled partly by autophagy. Besides proteostasis and organelle maintenance, other factors that are accepted hallmarks of aging, such as nutrient sensing and genomic instability are under the control of or elicit the activation of autophagy, making autophagy a major counter-regulatory process that supports skin homeostasis and healthy aging.

The skin provides several examples to illustrate the two main interactions between autophagy and aging: (1) Autophagy decreases the rate of aging and (2) the activity of autophagy declines during aging. Autophagy suppresses aging in a cell-autonomous manner by maintaining intracellular homeostasis and in a non-autonomous manner by contributing to various cell features that protect other cells. For instance, autophagy supports the differentiation of epithelial cells which allows them to protect other cells against the external environment. Since autophagy achieves the removal and recycling of intracellular material only to a certain extent, potential toxic cell components and dysfunctional lysosomes tend to accumulate during the life-time of cells. Some of the compromised cells succumb to cell death whereas others remain alive but lose their capacity to execute intracellular processes, including autophagy, with full efficiency. Loss and dysfunction of cells manifest in aging.

Long-lived and mostly quiescent stem cells require autophagy for intracellular homeostasis and for continuous ability to supply functional progeny cells. Inherent decline or exogenous suppression of autophagy leads to stem cell loss by competition, differentiation, or cell death. In short-lived differentiating cells, autophagy also contributes to intracellular homeostasis, however, autophagic activity needs to be maintained only over a short time for these cells to be functional. Nevertheless, autophagy defects can be inherited from the long-lived precursor cells (stem cells) and potentially compromise processes such as the defense against microbes, the release of cytokines, and most importantly, the protection against stress factors from the environment. In long-lived differentiated cells, autophagy contributes to the maintenance of cell survival and function. A decrease of autophagy leads to the accumulation of damaged or even toxic components and/or energy crisis. These disturbances of intracellular homeostasis impair the processes essential for cell functions and eventually lead to a loss of these cells.

Link: https://doi.org/10.3389/fcell.2019.00143

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Live Foreverish Podcast: Powering Up Your Health With Astaxanthin

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Live Foreverish Podcast: Powering Up Your Health With Astaxanthin

Did you know that astaxanthin has an antioxidant capacity that is up to 6,000 times greater than Vitamin C by some measures? 1 Astaxanthin is a potent antioxidant loaded with health benefits, largely due to its role as an antioxidant and an anti-inflammatory. Astaxanthin has been shown to provide distinct health benefits that have been clinically validated by research.

Learn what this ocean or freshwater-derived nutrient can do for your health with Dr. Michael Smith and his guest, author Bob Capelli. The podcast episode is available for download or you can listen now on LiveForeverish.com

In this episode, you’ll find out:
– What form to take
– What dose to take
– The top 3 reasons to take astaxanthin

Bob Capelli has been involved in natural healing and herbology for over thirty years. He is the lead author of five books, including a book on astaxanthin called “Natural Astaxanthin: The Supplement You Can Feel,” as well as dozens of articles for trade and consumer publications and scientific papers for peer-reviewed technical journals.






About Live Foreverish: Join Dr. Mike and Dr. Crystal as they sit down with some of today’s leading medical, health and wellness experts to discuss a variety of health-related topics. From whole-body health to anti-aging and disease prevention, you’ll get the latest information and helpful advice to help you live your life to the fullest. If you like what you hear, please take a moment to give Live Foreverish a 5-star rating on iTunes!

1. Carotenoid Science. 2007;11(6):16-20.

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A Large Polypill Clinical Trial Shows a Third Reduction in Cardiovascular Events

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The research and medical communities are slow to undertake work on combination therapies. Regulation makes it exceedingly expensive to assess multiple combinations, and there are numerous other perverse incentives to challenge any effort to build combination therapies with components developed and manufactured by different groups. Short of working around the existing system of regulation, and methods of doing this at scale are lacking at the present time, this is a challenging problem to solve. People follow incentives. Given this, it it is entirely plausible that there are many largely unexplored instances in which existing classes of medication for age-related disease might synergize to be more effective together.

In this context, clinicians and researchers have been discussing polypills for quite some time. The term polypill usually means a combination of existing treatments for cardiovascular disease such as statins to reduce blood cholesterol, ACE inhibitors to lower blood pressure, diuretics to reduce fluid retention, and so forth. The data to date strongly suggests that many reasonable polypill combinations will improve upon single medication use, and possibly do so at lower overall doses, and thus with lower side-effects.

Here, researchers report on a recent large clinical trial of a polypill, carried out in a comparatively poor population who are largely without access to the panoply of medications available in wealthier regions. The effect size is about what one would expect: in the world of the immediate past in which no-one was trying to tackle the causes of aging, and thus comparatively little can be achieved, reductions in blood cholesterol and blood pressure have been outstanding successes. Reducing cardiovascular mortality by a third without in any way addressing the underlying causes of cardiovascular mortality is quite the feat. In the immediate future, when senolytic drugs and other therapies that do address the causes of aging start to become widely used, we should expect to see much larger beneficial changes in population health.

Four-in-one pill prevents third of heart problems


A daily pill containing four medicines can cut the number of heart attacks and strokes by a third, a study shows. The polypill contains blood-thinning aspirin, a cholesterol-lowering statin, and two drugs to lower blood pressure. The researchers said the pill had a huge impact but cost just pennies a day. They suggest giving it to everyone over a certain age in poorer countries, where doctors have fewer options and are less able to assess individuals.

The study was based in more than 100 villages in Iran and about 6,800 people took part. Half the people were given the polypill and advice on how to improve their lifestyle, with the other half just getting the advice. After five years there were 202 major cardiovascular events in the 3,421 people getting the polypill and 301 in the 3,417 not getting the pill. The polypill led to large reductions in bad cholesterol but had only a slight effect on blood pressure, the study showed. The drug was given to people over the age of 50 whether they had had a previous heart problem or not.

In the UK and other wealthier countries doctors have the time to assess the needs of individual patients and a wide choice of different drugs, such as statins, to chose from. “In the UK, the advantages would be more marginal and you would probably want a clinical trial to see any benefits over what is offered at the moment.”

Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial


The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50,045 participants aged 40-75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation.

The non-pharmacological preventive interventions (including educational training about healthy lifestyle – eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12.5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome – occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke) – was centrally assessed by the GCS follow-up team.

We enrolled 6838 individuals into the study – 3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. During follow-up, 301 (8.8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5.9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0.66). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0.43). The frequency of adverse events was similar between the two study groups.

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Resveratrol’s role in achieving optimal health

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Have you heard of the so-called “French paradox?” It refers to the fact that despite their high cholesterol and high saturated fat diet, the French do not develop cardiovascular diseases because of their high red wine intake.1 While this belief most likely stemmed from a marketing campaign perpetuated by the wine industry,2 there may be some truth to this, as red wine contains a potent antioxidant known as resveratrol.3

However, drinking red wine is not the only way to get resveratrol, and you should not rely on it as your primary source of this antioxidant as it can pose negative effects due to its alcohol content. But first, let’s touch on what resveratrol is and how it may do your body good.

What is resveratrol?

Resveratrol, also known as 3,4′,5-trihydroxystilbene, is a naturally occurring compound found in a number of plants. It belongs to stilbenes, a class of polyphenolic compounds, and acts like an antioxidant. It may be a chemopreventive agent as well.4 Resveratrol is actually designed to help increase the life span of these plants by making them resistant to diseases, injury and various stressors, including excessive UV radiation, drastic climate changes and fungal infections.5,6

The discovery of resveratrol can be attributed to Japanese scientist Michio Takaoka, who first isolated the compound in 1939.7 He took it from the rhizomes of the white hellebore (Veratrum grandiflorum Loes),8 which thrives in the Nagano Prefecture.9

Many years later, in 1963, another Japanese scientist known only as Nonomura isolated resveratrol from Japanese knotweed.10 In traditional Chinese medicine, this herb has been used for many centuries to help ease cough, treat jaundice and manage hepatitis.11 Knotweed is known to have the highest resveratrol concentration among plant sources.12

It was only in 1976 that the presence of resveratrol in grapes became known,13 and only in 1992 was it discovered to be in wine.14 More studies regarding the potential benefits of resveratrol are still being conducted.

Ditch the wine: Here are other food sources of resveratrol

You can get resveratrol from a number of plant foods, but most people believe the misconception that they can simply drink red wine to reap the benefits of this potent antioxidant. But as mentioned above, this can pose unwanted adverse health effects.

Although some studies claim that resveratrol is highly soluble in alcohol,15 making it more absorbable in red wine, this should not be reason enough to rely on wine as your main source. First of all, alcohol is a neurotoxin that can severely damage your brain, heart and other organs.16 Plus, it increases your insulin levels.17

Some wines and other alcohol beverages like beer have also been shown to be contaminated with glyphosate,18 the active and carcinogenic ingredient in Roundup herbicide. Hence, I would advise you to get this compound from healthier food sources or to take a resveratrol supplement.

Muscadine grapes are known to have high resveratrol concentrations.19 Most of the antioxidants in grapes, including resveratrol, are found in their skins and seeds.20 In fact, one gram of fresh grape skin contains at least 50 to 100 micrograms of resveratrol.21 Other potent sources of this nutrient include:22

The problem with most of these food sources, specifically the grapes and berries, is that they’re particularly high in fructose. Consuming them in excessive amounts may prove to be detrimental to your glucose levels, especially if you are insulin resistant.

In addition, if you want to get resveratrol from cacao, make sure that you consume organic dark chocolate or raw cacao, and not the milk chocolate varieties that are loaded with sugar. Another potent, yet lesser-known, source of resveratrol is itadori tea, made from Japanese knotweed. It has a long history of use as a traditional herbal remedy by the Chinese and Japanese, and is said to help protect against stroke and heart disease.25

If you aren’t receiving enough resveratrol from food sources such as these, I recommend taking a high-quality resveratrol supplement. Ideally, look for a whole food complex that makes use of muscadine grape skin and seeds.

What are the benefits of resveratrol?

As an antioxidant, resveratrol is known for combating damaging free radicals in your body.26 However, its benefits go beyond that, as it has been found to have anti-inflammatory and anticarcinogenic properties as well.27 That’s why this potent compound may be highly useful for helping to fight and reduce the risk of a variety of chronic illnesses.28

One of the standout benefits of this potent antioxidant is its neuroprotective effects, which may help slow or prevent the progression of Alzheimer’s disease, vascular dementia and stroke.29 Resveratrol supplements can cross your blood-brain barrier to quell inflammation in your central nervous system.30 This type of inflammation actually plays an important role in the development of neurodegenerative illnesses.31

Resveratrol also shows promise in improving cerebral blood flow,32 which is responsible for its protective effects against stroke and vascular dementia. To summarize, here are some of the effects that resveratrol can have on your brain (and overall) health:

  • May help protect against depression33
  • Helps improve brain blood flow34
  • Helps suppress brain inflammation35
  • May inhibit plaque buildup, which may lead to Alzheimer’s36
  • Has antioxidant and antimicrobial properties37
  • May improve learning, mood and memory38

Another impressive way that resveratrol can boost your well-being is its ability to improve mitochondrial health. According to a study published in the journal Nature, mice that are on a high-calorie diet exhibited better health and a higher survival rate after taking resveratrol.39

In another study, it was found that improved mitochondrial health through resveratrol helped protect against metabolic disease, diet-induced obesity and insulin resistance. It does this by activating SIRT1 and PGC-1alpha, which are the primary drivers for mitochondrial biogenesis.40 And, at least one other study showed that resveratrol may improve glycemic control and decrease insulin resistance.41

Resveratrol may have potential benefits against cancer

There is a growing number of studies that support resveratrol’s potential effects on cancer, with evidence dating as far back as 1997.42 Cancer researchers took great interest in these findings, particularly resveratrol’s ability to make cancerous tumors more vulnerable to conventional cancer treatments like chemotherapy and radiotherapy.43

A 2011 review of dietary agents that have tumor-sensitizing properties (making them more susceptible to chemo drugs) found that resveratrol was a clear candidate owing to its multitargeting properties.44 Some cancers that resveratrol may have a substantial effect on include:

  • Prostate cancer45
  • Acute promyelocytic leukemia46
  • Lung carcinoma47
  • Multiple myeloma48
  • Pancreatic cancer49

A 2011 study notes that resveratrol may help alleviate some of the debilitating side effects of chemotherapy and radiotherapy, which include depression, fatigue, anorexia, neuropathic pain and sleep disorders, to name a few. The authors noted that these symptoms occur due to “dysregulation of inflammatory pathways” in your system, which explains the efficacy of this antioxidant.50

Are there side effects of resveratrol?

Resveratrol is generally safe and, according to WebMD,51 there are no severe side effects associated with this supplement, even in high doses. However, it’s still best to exercise caution and consult with your physician before taking this supplement.

You should also be careful if you’re taking drugs to manage a disease. Resveratrol may interact with and increase the effectiveness of medications like blood thinners and NSAIDs, so refrain from taking this supplement if you’re using these prescription drugs.52 In fact, resveratrol has been noted to inhibit aggregation of platelets in high-risk patients who are resistant to aspirin.53

Do not give this supplement to children, as well as pregnant or breastfeeding women, without the advice of a health practitioner.

Resveratrol can reap benefits with a solid nutritional basis

The benefits of resveratrol can be far-reaching, but take note that taking it will be useless if you do not address your overall diet and lifestyle. Make sure that you cover the basics, such as consuming healthy, well-balanced meals, following a regular exercise routine, managing your stress and getting sufficient sleep.

As with other supplements, resveratrol only serves as a complement to your diet and should not be treated as a solution or cure to your health problems.

Frequently asked questions (FAQs) about resveratrol

Q: What does resveratrol do?

A: Resveratrol is a polyphenolic compound that naturally occurs in plants. It works as a potent antioxidant that makes plants resistant to diseases, injury and various stressors, including excessive UV radiation, drastic climate changes and fungal infections. Hence, it is said that when you consume resveratrol, you also get the antioxidant and anti-inflammatory effects that it offers.54,55

Q: What is resveratrol used for?

A: Resveratrol is basically used to help combat damaging free radicals in the body.56 It has shown promise against chronic illnesses, and has a particularly potent neuroprotective effect, offering protection against diseases like vascular dementia, Alzheimer’s disease and stroke.57 It’s also shown promise in boosting mitochondrial health58 and may even have anticancer benefits.59,60

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Visceral Fat Tissue is Anti-Inflammatory in Lean Mice, Inflammatory in Fat Mice

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Excess visceral fat tissue leads to chronic inflammation via a range of mechanisms that include the creation of more senescent cells than would otherwise exist. Senescent cells secrete a potent mix of inflammatory and other signals that degrade tissue function in many ways. Since the accumulation of lingering senescent cells is a cause of aging, being overweight doesn’t just increase risk and severity of age-related disease, and shorten life expectancy, but also literally accelerates aging. The more fat tissue, the worse the outcome over the long term. As this paper points out, however, this is only the case for excess visceral fat tissue. When lean, the normal, smaller amounts of this tissue are actually anti-inflammatory and beneficial.


Adipose tissue is host to various immune cells and it is well established that during obesity, the amount of inflammatory macrophages increase in adipose tissue. Visceral adipose tissue (VAT), surrounding the inner organs, has been shown to be more inflammatory active than subcutaneous adipose tissue (SAT), as increased amounts of visceral/abdominal fat associates with high levels of circulating inflammatory markers and a high number of pro-inflammatory cells in their adipose tissue.

Interestingly, in human and rodent studies, ageing is associated with an increase in the amount of visceral adipose tissue and/or level of inflammation. It is, however, unclear to what extent these age-related changes are a result of ageing per se or rather the result of changes in life-style with e.g. reduced levels of physical activity without a corresponding reduction in caloric intake. A human cross sectional study reported that whereas ageing is associated with increased inflammation, life-long endurance training resulted in lower circulating levels of inflammatory markers in both young and elderly individuals.

In the current study, we wanted to investigate the inflammatory status and tissue integrity of VAT in an exercise-training model of lean adult and old mice. We randomized adult (11 months; n = 21) and old (23 months; n = 27) mice to resistance training or endurance training, or to a sedentary control group. Strikingly, we observed an anti-inflammatory phenotype in the old mice, consisting of higher accumulation of anti-inflammatory M2 macrophages and IL-10 expression, compared to the adult mice. In concordance, old mice also had less VAT mass and smaller adipocytes compared to adult mice. In both age groups, exercise training enhanced the anti-inflammatory phenotype. In conclusion, in the absence of obesity, visceral adipose tissue possesses a pronounced anti-inflammatory phenotype during aging which is further enhanced by exercise.

Link: https://doi.org/10.1038/s41598-019-48587-2

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Methods of Inducing Cellular Damage are Rarely Relevant to Aging, and the Details Matter

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One of the major challenges in aging research is determining whether or not models of cellular or organismal damage and its consequences are in any way relevant to the natural processes of aging. One can hit a brick with a hammer, but that says very little about how bricks weather over the years. One can hit the brick very carefully with the hammer in ways that produce results that look weathering-like, but can that be used to tell us anything about weathering? In cells the line between artificial and natural damage can be hard to pin down, but the fine details of the processes involved always matter. It is easy to break cells and see them become dysfunctional as a result, but hard to determine the relevance of that breakage to natural aging. Even in the example here, in which researchers are trying to achieve something very similar to the consequences of excessive oxidative damage in mitochondria that is observed in aging, it is possible to argue that the methodology used has little relevance to the actual damage of aging in its details, and therefore may not be a useful model.


Researchers have carried out a causal experiment to kick off a mitochondrial chain reaction that wreaks havoc on the cell, all the way down to the genetic level. “I like to call it ‘the Chernobyl effect’ – you’ve turned the reactor on and now you can’t turn it off. You have this clean-burning machine that’s now polluting like mad, and that pollution feeds back and hurts electron transport function. It’s a vicious cycle.” The researchers used a new technology that produces damaging reactive oxygen species – in this case, singlet oxygen – inside the mitochondria when exposed to light. “That’s the Chernobyl incident. Once you turn the light off, there’s no more singlet oxygen anymore, but you’ve disrupted the electron transport chain, so after 48 hours, the mitochondria are still leaking out reactive oxygen – but the cells aren’t dying, they’re just sitting there erupting.”

At this point, the nucleus of the cell is being pummeled by free radicals. It shrinks and contorts. The cell stops dividing. Yet, the DNA seems oddly intact. That is, until the researchers start looking specifically at the telomeres – the protective caps on the end of each chromosome that allow them to continue replicating and replenishing. Telomeres are extremely small, so DNA damage restricted to telomeres alone may not show up in a whole-genome test, like the one the researchers had been using up to this point. So, to see the genetic effects of the mitochondrial meltdown, the researchers had to light up those tiny endcaps with fluorescent tags, and lo and behold, they found clear signs of telomere fragility and breakage. Then, in a critical step, the researchers repeated the whole experiment on cells with inactivated mitochondria. Without the mitochondria to perpetuate the reaction, there was no buildup of free radicals inside the cell and no telomere damage.

Link: https://www.upmc.com/media/news/082619-pnas-van-houten

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Age Gracefully with PQQ (Pyrroloquinoline Quinone): An Undervalued Anti-Aging Nutrient

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Age Gracefully with PQQ (Pyrroloquinoline Quinone): An Undervalued Anti-Aging Nutrient
Juanita O. Enogieru – Life Extension Wellness Specialist

The human body functions through a multitude of pathways. It is a highly complex organism with an abundance of spinning wheels, each requiring fuel for healthy function. Thus, there are a variety of nutrients that you can include in your dietary supplement regimen that will help support your body’s ability to heal and repair damage and modulate dysfunctional pathways. Considering this fact, it is easy to understand why people have so many questions about which nutrients are critical for promoting graceful aging. This means giving your body nutrients that can enhance quality of life. But you may be asking yourself, where do I begin?

Let’s start with supporting the powerhouse of each cell, the mitochondria. Mitochondria are organelles that reside in our cells and where ATP (adenosine triphosphate) is manufactured. ATP is a source of energy that fuels the majority of metabolic reactions in our bodies. Energy-intensive organs such as the brain, heart, kidneys and skeletal muscles are rich in mitochondria. In fact, human cells may house anywhere from one to thousands of mitochondria, depending on the type of tissue and other factors.1 With age, the number and function of mitochondria decline significantly, which may result in accelerated aging and noticeable declines in cognitive, metabolic, skin, immune, neurological, reproductive and cardiovascular health.2-4

To target key characteristics of aging, it is imperative to supply the body with nutrients that support the mitochondria and energy-producing pathways.

What can cause a cell to become dysfunctional?

Most cellular functions require a continual supply of energy from mitochondria for essential activities such as growth, repair and reproduction. An important feature of mitochondrial dysfunction is a decrease in the number of mitochondria, as well as inefficient energy production due to decreased functionality.5 Mitochondria are vulnerable to damage from oxidative stress. Most people are aware that toxins in the environment can enter the body and generate free radicals that can attack cells. However, during the energy making process, free radicals are also produced.

The mitochondrial free radical theory of aging suggests that during energy production, oxidative stress occurs due to the natural production of free radicals, or reactive oxygen species (ROS), which can damage proteins and lipids and cause mutations in mitochondrial DNA. It is theorized that these alterations cause dysfunction and aging.6 Because mitochondria have their own DNA, they can grow and reproduce independently within the cell; however, mitochondrial DNA does not have many defenses against free radical damage and is highly susceptible to attack.7

Aging is accompanied by declining levels of cellular mitochondria, which leads to less ATP production. When mitochondrial numbers and functionality decline and less energy is produced, cells become dysfunctional, increasing their chance of death. The more functional mitochondria you have in your cells, the greater your overall health and sturdiness.

How can PQQ support healthy aging?

Pyrroloquinoline quinone (PQQ) is a potent antioxidant found in plant matter. We consume minute amounts of it in foods like green soybeans, oranges, tomatoes, celery and apples. Higher amounts are provided in parsley, green and oolong tea, natto (fermented soybeans), green peppers, papaya, kiwi and tofu. PQQ is even present in breast and cow’s milk. Americans tend to consume these foods sporadically or seasonally, and in moderate to minimal quantities. However, research is showing that PQQ plays a vital role in the growth and development of humans and animals.8

One of the most exciting things about PQQ is that it may support the growth of new mitochondria, as seen in animal studies.9 It can activate genes that induce the growth of new mitochondria.10 Previously, we were only aware that strenuous exercise and caloric restriction could induce this effect.11

In addition to boosting mitochondrial numbers, PQQ is a unique substance that is efficient in sustaining antioxidant capacity. PQQ can protect the mitochondria through its antioxidant-scavenging properties, and its ability to activate genes that regulate mitochondrial repair for fixing damaged DNA.12 PQQ has also been shown to improve oxygen utilization in the mitochondria, counteracting another underlying factor of mitochondrial dysfunction.13

What are the benefits of supplementing with PQQ?

Research has shown that PQQ supports healthy cognition in older adults by preventing decline in brain function, attention and working memory.14 It can also lower inflammation by modifying the activation of pro-inflammatory enzymes and lowering CRP (C-reactive protein), a marker of systemic inflammation.15 PQQ was also shown to slow the progression of rheumatoid arthritis in a preclinical study.16 In other preclinical studies, it has supported cardiovascular, immune and neurological health.17

Who should supplement with PQQ?

It’s simple, ALL aging adults could benefit from PQQ. And yes, PQQ is a supplement that you can safely use regularly. However, due to variances in biochemistry, the most suitable dosage may vary from person to person.

Can I get enough PQQ from my diet?

Cells deprived of PQQ show signs of mitochondrial dysfunction. However, as little as 200 to 300 mcg of PQQ/kg in the diet was able to reverse dysfunction in a mouse model.9 Consider the fact that one of the richest sources of PQQ, natto (fermented soybeans), contains approximately 61 ng/g wet weight (0.061 mcg/g). This is much less than what is needed to stimulate the growth of new mitochondria. Since concentrations are mostly low in food sources, if you want to modulate brain aging and reduce inflammation, taking a supplement could be ideal.

What dose of PQQ should I take daily?

Higher dosages are supportive for individuals at an increased risk for mitochondrial dysfunction, such as older adults and individuals with health concerns. A study using 20 mg of PQQ showed improvements in cognitive function with no adverse effects.14 Conversely, a younger individual who wants to support healthy aging may benefit from 10 mg of PQQ. PQQ has been shown to have low oral toxicity in rats, meaning that no adverse effects were noted for doses much higher than 20 mg of PQQ.18

By simply giving your body nutrients it needs at optimal doses, you can supply your energy-creating pathways with the tools needed to promote overall health and well-being.

Synergistic nutrients: What compliments PQQ?

Since the body thrives when you provide it with various nutrients, it may be advisable to pair PQQ with ubiquinol CoQ10 and the vitamin B3 metabolite, nicotinamide riboside (NR).

Coenzyme Q10 (CoQ10) is an antioxidant that is produced in the liver via the cholesterol pathway and is an essential cofactor in many biochemical pathways in the body, including the production of ATP in the mitochondria. In fact, CoQ10 is a critical player in the synthesis of ATP and in promoting mitochondrial function.19 The natural production of CoQ10 is known to decline during the aging process and/or with statin medication use.20 When cells lack sufficient CoQ10, mitochondrial dysfunction sets in and can lead to impaired organ function (heart, liver, kidneys, etc.), damaged blood vessels and poor circulation.21

Based on the totality of published research about CoQ10, it may be desirable for adults over the age of 30 to seek a minimum sustained blood level of more than 3 mcg/mL of blood. Maintaining blood levels up to 7 mcg/mL may support healthy aging and heart health.22 A blood test will help you figure out the dose most suitable for your biochemistry. To maximize absorption, we highly suggest the ubiquinol form of CoQ10. Ubiquinol CoQ10 has a much higher bioavailability and provides potent support at lower dosages than the ubiquinone form of CoQ10.22 Optimal blood ranges may be reached by supplementing with 100-400 mg of ubiquinol daily.

The non-flushing vitamin B3 metabolite, nicotinamide riboside (NR), converts to an essential factor in energy production in cells, nicotinamide adenine dinucleotide (NAD+). NR supplementation can raise circulating NAD+ levels in humans.23 NAD+ may help promote healthy aging by mitigating mitochondrial dysfunction by enhancing cellular energy production and boosting the function ofmitochondria. Preclinical studies show that restoring mitochondrial function with NR slows aging and extends longevity.24 Furthermore, NR has been shown to improve markers of inflammation and mitochondrial function in preclinical cell studies.25,26

Pairing PQQ with mitochondrial supporters such as CoQ10 and NR will provide the body with vital tools needed to fuel functions in the body that require energy. Considering the wide-ranging benefits of PQQ, it seems that any person seeking to stimulate the production of new mitochondria, reduce inflammation, support mitochondrial DNA repair and other vital metabolic functions that promote healthy aging should include the undervalued nutrient PQQ in their dietary supplement regimen today.

About the author: Juanita Enogieru is a nutritionist and Life Extension Wellness Specialist working with the community to build healthy and balanced nutritional habits. While pursuing an education in medicine and attempting to help her body heal, it became apparent that there was a gap in medical practices with regard to nutrition and an abundance of misinformation about balanced nutritional practices. After obtaining a bachelor’s degree in health education from the University of Florida, she worked with non-profit organizations to deliver nutrition education to community members. Wanting to learn more about nutrition and how herbs could be used to help the body heal, she pursued a master’s degree in dietetics and nutrition and shortly after began working with Life Extension. With the understanding that everyone has a unique biochemical individuality, it is vital to address each individual based on their specific needs and biochemical make-up. Her mission now is to offer guidance, support and education to individuals based on balanced nutritional insights that address the mind, body and spirit.

References:

  1. Front Cell Dev Biol. 2016;4:85.
  2. Mol Cell. 2016;61(5):654-666.
  3. Aging Cell. 2018:e12793.
  4. Genes (Basel). 2017;8(12)
  5. Integr Med (Encinitas). 2014;13(4):35-43.
  6. Prog Mol Biol Transl Sci. 2014;127:1-27.
  7. Biochim Biophys Acta. 2012;1819(9-10):979-91.
  8. J Biosci. 2012;37(2):313-25.
  9. J Nutr. 2006;136(2):390-6.
  10. Biochemistry. 2017;56(50):6615-6625.
  11. Exerc Sport Sci Rev. 2014;42(4):169-74.
  12. Neuroscience. 2014;270:183-91.
  13. J Biol Chem. 2010;285(1):142-52.
  14. Adv Exp Med Biol. 2016;876:319-325.
  15. J Nutr Biochem. 2013;24(12):2076-84.
  16. Inflammation. 2016;39(1):248-256.
  17. Biosci Biotechnol Biochem. 2016;80(1):13-22.
  18. Regul Toxicol Pharmacol. 2014;70(1):107-21.
  19. J Am Coll Nutr. 2001;20(6):591-8.
  20. Front Physiol. 2018;9:44.
  21. Biology (Basel). 2019;8(2)
  22. Biofactors. 2008;32(1-4):119-28.
  23. PLoS One. 2017;12(12):e0186459.
  24. Biogerontology. 2019
  25. Nutr Res Pract. 2019;13(1):3-10.
  26. Biochemistry (Mosc). 2018;83(7):800-812.

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Reduced TGF-β and Increased Oxytocin Reverses Measures of Aging in Old Mice

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Numerous research and development initiatives have emerged from the heterochronic parabiosis studies of the past decade or more, in which an old and a young mouse have their circulatory systems linked. Researchers have moved on from the initial experiments to the search for circulating factors in blood that change in ways that are harmful in aged individuals, and which might be adjusted to improve cell and tissue function. This area of research is one of many to explore the question of how much of degenerative aging is the result of (a) direct consequences of molecular damage versus (b) the result of inappropriate cellular reactions to the existence of damage, the latter mediated to some unknown degree by signaling carried in the bloodstream.

Is it possible to ignore the damage and extend healthy life just by suppressing the reactions to damage? It would be very strange if the answer were that this works comprehensively and damage never has to be repaired. Further, the consequences of any given form of underlying damage can be thought of as a network of diverse chains of cause and effect spreading from a single root: it will require far more work to identify and address all of these reactions to damage than to focus down on a means of repairing the damage. Still, and unfortunately, the concept of damage repair, striking at the root of aging, remains a comparatively unpopular strategy in the research community for some reason. Near all work on the treatment of aging is focused on tinkering with the downstream consequences of damage, and therefore probably a highly inefficient use of funds and time, even given the successes that arise.

One of the more noted scientific teams involved in parabiosis research here report on their recent work, opening this open access paper with a bold statement on the degree to which they believe aging to result from signaling changes, reactions to damage. They are focusing down on just a few signaling factors in the bloodstream, TGF-β and oxytocin, and finding ways to alter amounts in circulation in comparative isolation, without adjusting other factors as well. Given that earlier work on GDF-11 as circulating signal involved in cellular responses to aging has resulted in a great deal of ongoing research and at least one biotech startup, the results here seem interesting enough to drawn in funding for further, similar projects.

Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age


We hypothesize that altered intensities of a few morphogenic pathways account for most or all the phenotypes of aging. In heterochronic parabiosis, a young and old animal are surgically connected to share a common blood circulation. Experiments in mice showed this shared circulatory milieu restored tissue health and regeneration of the old partner; and at the same time, the young partner experienced a regenerative decline in a number of tissues. However, parabiosis is not clinically translatable and infusion of young blood or plasma into old mammals is controversial and fraught with multiple side-effects. Blood fractionation is typically cumbersome, and it is inherently complicated by the fact that the rejuvenative activities are likely to be contained in multiple molecularly different fractions. Plus, the assays for determining such activity are themselves complex, thus adding to the hurdles of a screen for active blood molecules. With these observations to consider, what would be the key set of molecular parameters that were changed by the blood heterochronicity and what would be the best translational way forward?

The changes that manifest with aging include altered cell metabolism, increased Reactive Oxygen Species (ROS), inflammation, senescence, and decline in immune function. However, from the viewpoint of tissue maintenance and regeneration, we postulated that these arise from changes in tissue growth and homeostasis and specifically in key signaling networks regulating stem cells and their differentiated niches. In support of this idea, pathway modifier-based approaches for the enhancement of aged tissue repair and maintenance have been reported, for example, by systemic delivery of OT which induces MAPK/pERK signaling, by forced activation of Notch-1, by antagonism of TGF-beta/pSmad signaling, or by antagonism of the Jak/Stat pathway.

The highest risk from modulating key cell-fate regulatory signaling pathways come from changing levels too far above or too far below normal healthy levels. Such drastic alterations result in severe multi-tissue side-effects. But high levels of a single modifier might be required to overcome the many age-specific molecular changes. For example, ectopic oxytocin (OT) might be needed at a considerably high dose to overcome age-elevated TGF-beta 1. And, the Alk5 inhibitor (Alk5i) of the TGF-beta receptor might be needed at high dose to overcome the lack of OT and other hormones with age.

Using a two-prong approach of simultaneously diminishing TGF-beta signaling and adding OT (which activates pERK via the oxytocin receptor (OTR)), we were able to reduce the required dose of Alk5i, shorten the duration of treatment and to achieve a more broad rejuvenation of the three germ-layer derivative tissues: brain, liver and muscle. And, we found that Alk5i+OT downregulated the number of cells that show an age-associated increase of the cyclin dependent kinase (CDK) inhibitor and marker of senescence, p16, thereby representing a pharmacological combination of two FDA approved drugs to normalize this checkpoint protein, which when chronically elevated negatively impacts tissue health.

Translationally, this study points toward a pharmacological approach to rapidly enhance the health and maintenance of multiple old tissues. Here we focused on a few key age-related parameters of the three germ layer tissues: neurogenesis and neuroinflammation of the brain, regeneration and fibrosis of the skeletal muscle and adiposity and fibrosis of the liver. In future work if would be interesting to study how these seemingly unrelated aging features become rapidly rejuvenated by A5i+OT, and if additional phenotypes, such as muscle innervation, neural plasticity, metabolism, etc. also become improved in old animals. The observed rejuvenating effects are at least as robust as, and act faster than, heterochronic parabiosis.

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Clearing Dysfunctional Microglia Prevents Formation of Amyloid-β Plaques in a Mouse Model of Alzheimer's Disease

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It is becoming clear that dysfunction in the supporting immune cells of the brain, the microglia, is important in the progression of neurodegenerative conditions such as Alzheimer’s disease. This certainly involves microglia becoming senescent, as demonstrated by the ability of senolytic treatments to reverse pathology in animal models of Alzheimer’s disease. But it most likely also involves a more subtle shift in the behavior of microglia, from a more regenerative M2 polarization to a more inflammatory and aggressive M1 polarization.

Both classes of microglial behavior are necessary in the grand scheme of things, but aging appears to be accompanied by an excess of M1 and too few M2 microglia (and macrophages as well, which have a similar set of behaviors) in most circumstances and tissues examined to date. The causes of this shift in cell behavior are barely explored at this point; it is unclear how it relates to the underlying molecular damage that drives aging. Nonetheless, it is certainly harmful.


Alzheimer’s disease (AD) is a progressive, age-related neurodegenerative disorder thought to be triggered by the appearance and build-up of amyloid-β (Aβ) plaques in the cortex. Genome-wide association studies have identified numerous genes that confer increased risk for developing the disease; however, the mechanisms underlying plaque formation remain unclear. Within the central nervous system (CNS), microglia perform homeostatic maintenance, immune-related, and phagocytic functions. Their reported capacity for Aβ phagocytosis and clearance led to the suggestion that age-related changes in microglial function reduce clearance of neuronally derived Aβ from the brain, thus allowing plaque formation.

We and other groups report that following the initial period of plaque formation, microglia surround the plaques and subsequently mount a harmful and non-resolving inflammatory response. Despite this response, however, Aβ clearance and plaque modulation/dynamics is unaffected, yet the removal of the microglia at advanced stages of pathology protects against synaptic and neuronal loss.

Here, we set out to explore the contributions of microglia to plaque formation in the initial stages of the disease, which requires prolonged depletion of microglia throughout the plaque-forming period. To that end, we designed, synthesized, and optimized a potent, specific, orally bioavailable, and brain-penetrant CSF1R inhibitor, PLX5622, to deplete microglia for more than 6 months in 5xFAD mice. With the elimination of microglia, we uncovered critical roles of these cells in plaque formation, compaction, and growth, mitigating neuritic dystrophy, and modulating hippocampal neuronal gene expression in response to Aβ pathology.

Ultimately, these data demonstrate that microglial elimination is associated with the prevention of plaque formation and the downregulation of hippocampal neuronal genes that occur in a preclinical model of AD progression. These results indicate that microglia appear to contribute to multiple facets of AD etiology – microglia appear crucial to the initial appearance and structure of plaques, and following plaque formation, promote a chronic inflammatory state modulating neuronal gene expression changes in response to Aβ/AD pathology.

Link: https://doi.org/10.1038/s41467-019-11674-z

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