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Considering the Experience of Being One of the Last Mortals

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With the development of rejuvenation therapies underway, and accelerating, somewhere ahead lies a dividing line. Some people will be the last to age to death, too comprehensively damaged for the technologies of the time to recover. Everyone else will live indefinitely in youth and health, protected from aging by periodic repair of the underlying cell and tissue damage that causes dysfunction and disease. Where is that dividing line? No one can say in certainty. I look at the children of today, with long lives ahead of them, and find it hard to believe that in a hundred years the problem won’t be solved well in time for them to live for as long as they choose. Equally, people in middle age today will certainly benefit greatly from the advent of first generation rejuvenation technologies, such as senolytics, each narrowly focused on one mechanism of aging. Yet I’m skeptical that matters will progress rapidly enough to rescue them. So somewhere between those two points are the people on the very edge; the last mortals.

In a sense this isn’t terribly profound at all. It is the same story for every as yet uncontrolled medical condition, where the medical research community is working towards effective treatments that will arrive at some uncertain future date. There will be those who are the last to die, just as the therapies that save everyone else are rolling out. It is only the magnitude that is greater in the case of aging – a hundred or a thousand times greater. Does the fact that it affects everyone mean that there will be public disorder, disputes between the first immortals and the last mortals, where only private, personal existential crises exist today? I think claims of societal unrest as a result of the realization that your children will live indefinitely, while you yourself will not, are likely overwrought.

The Last Mortals

Ever-growing lifespans are the result of regular advances in medical science. In 1900 the three leading causes of death in the United States were pneumonia/influenza, tuberculosis, and diarrhoea. Only a century and a bit on, many of the major acute illnesses are tractable. Every month brings striking new medical advances. Increasingly, medical research is shifting from acute conditions such as influenza towards chronic conditions including diabetes and Alzheimer’s. Ageing is the ultimate chronic condition, and there seems to be no reason, in principle at least, that would prevent us from discovering a means of halting or reversing ageing itself.

What if that all happens sooner rather than later? But what if it’s not soon enough? Imagine that, after a few more breakthroughs, a scientific consensus emerges that we will have conquered illness and ageing by the year 2119; anyone alive in 2119 is likely to live for centuries, even millennia. You and I are very unlikely to make it to 2119. But we are likely to make it relatively close to that date – in fact, relative to the span of human history, we’ve already made it very close right now. Think that through, carefully. What would it mean to realize that you very nearly got to live forever, but didn’t? What would it mean if, in our looming senescence, we were increasingly forced to share social space with young people whose anticipated allotment of time massively dwarfs our own? We would then be the last mortals.

To be precise, the kind of immortality I have in mind can be called biological immortality. A biologically immortal organism does not die from illness or ageing – though they may still die in a plane crash. If humans acquired biological immortality, our expected lifespans would jump to enormous lengths. Almost everyone would still eventually die; statistics dictate that if you fly on planes every few weeks for eternity, eventually one will crash. This point allows us to sidestep one of the perennial questions about immortality: is endless life something we’d really want? What is distinctive for biological immortals is that death becomes only a possibility, an option, not an inevitability on a fixed timetable. This sort of immortality, I would think, is definitely not a curse. To have the option of living healthily a very long time, possibly for as long as one could want (but no longer), seems like an unmitigated blessing.

Until now, the wish for immortality was mere fantasy. No one has ever lived beyond 122 years, and no one has reasonably expected to do so. But what happens once the scientists tell us that we’re drawing near, that biological immortality will be ready in a generation or two – then what? Seneca told us to meet death cheerfully, because death is “demanded of us by circumstances” and cannot be controlled. Death’s inevitability is what makes it unreasonable to trouble oneself. Yet, as I’ve been arguing, soon death may cease to be inevitable. It may become an option rather than a giver of orders. And, as the fantasy of immortality becomes a reasonable desire, this will generate not only new sorts of failed desires, but also new ways to become profoundly envious.

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Green Tea Health Benefits and Safety

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Green Tea Health Benefits and Safety
Julia Dosik BS, MPH

Can green tea really make a difference in your health?

Out of all the teas produced from the leaves of the Camellia sinensis plant, green tea contains the highest levels of powerful nutrients called catechins (pronounced cat-eh-kins). There are eight main catechins found in green tea. Of them, the most notable is epigallocatechin gallate (EGCG), accounting for about 65% of all green tea catechins.1 These nutrients help provide cardiovascular and metabolic benefits, including green tea’s ability to support healthy weight. Therefore, it is no surprise that green tea is considered one of the healthiest drinks and supplements on the market.

Is green tea good for your heart?

Consuming green tea is correlated with improvements in blood pressure and cholesterol levels and reduction in body fat. In fact, one of the most reputable medical journals, Journal of the American Medical Association (JAMA), published a study showing that those who consumed more than fivecups of green tea daily experienced a 26% lower risk of death from cardiovascular events compared with people who drank less than one cup daily.2 In another study, when individuals with existing high blood pressure were given a beverage with green tea extract containing catechins, their systolic blood pressure was reduced by an average 9 mm Hg in 12 weeks.3 Imbalanced cholesterol levels are a huge risk factor for cardiovascular disease. When given green tea extract mixed with catechins for six weeks, obese and/or overweight women experienced a 4.8% decrease in LDL (“bad”) cholesterol.4 Thus, when it comes to cardiovascular benefits, it is evident that the research is on green tea’s side.

Can green tea reduce belly fat?

Many consumers seek out green tea to aid with weight loss—and for good reason. Research shows that when individuals consumed a green tea extract mixture with catechins daily for 12 weeks, they had about a 10% reduction in body fat (including visceral fat), as well as a 1-inch waist circumference reduction.3 Not bad from just consuming a natural plant extract daily!

What is matcha green tea?

Matcha is a type of green tea made by taking the young leaves and grinding them into a bright green powder. Matcha leaves grow on green tea bushes in Japan, but they are kept in the shade. Keeping them in the shade increases the amount of chlorophyll content, which is the pigment that gives the leaves their bright green color. In terms of catechin content, matcha also contains high amounts of EGCG.

What is the best way to consume green tea?

Although the pleasant taste of both matcha and regular green tea is a bonus for its consumption, one must drink large amounts of the tea to boost blood levels of the catechins for them high enough to provide these health benefits. Since it is not as common for people in Western cultures to consume the high amounts of green tea that is consumed in Eastern Asia, the development of potent green tea extracts has been on the rise. Concentrated green tea extracts are formulated in a way that retains high amounts of catechins, making them even more absorbable than green tea beverages alone. In fact, there is a novel green tea extract providing eight key catechins found in green tea. Taking one capsule daily is equivalent to drinking up to 12 cups of standard green tea!

Is green tea safe?

Green tea is generally regarded as safe to drink and supplement with. Individuals who are sensitive to caffeine may want to limit their daily intake or try a decaffeinated green tea beverage and/or supplement. Statements of green tea causing liver injury have made their way through the popular media. Despite concerning media headlines, the truth is that reports of green tea causing any injury are extremely rare. When taking an extract, do not exceed the recommended dose on the label. Green tea has been shown to be beneficial and safe in myriad studies. Life Extension continues to stand by the wide range of published research showing that green tea supports good health through various beneficial biochemical mechanisms.

Do I need green tea?

The benefits of green tea have been scientifically validated, so including it in your diet and/or supplement regimen is a sound choice. Green tea’s optimizing impact on cardiovascular health and weight reduction makes this powerful extract even more appealing to individuals looking to support their health in these areas—especially since cardiovascular disease and obesity are health concerns in the United States. Whether you are trying to match the JAMA-reported study and drink five cups of green tea per day, or you take a high-quality and potent green tea extract daily, there is no question that you will be providing your body with powerful catechins for overall body performance!

About the Author: Julia Dosik, BS, MPH, is a clinical corporate trainer at Life Extension headquarters in South Florida. She holds a Bachelor of Science in biology and psychology as well as a Master of Public Health specializing in health education. Julia utilizes a mix of in-person, virtual and written training to educate employees and consumers on how the human body functions and the importance of supplementing with science-backed ingredients. It is her deepest belief that high-quality dietary supplements are fundamental to an individual’s physical and mental well-being.


  1. Mancini E, Beglinger C, Drewe J, et al. Green tea effects on cognition, mood and human brain function: A systematic review. Phytomedicine. 2017Oct 15;34:26-37.
  2. Kuriyama S, Shimazu T, Ohmori K, et al. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA. 2006 Sep 13;296(10):1255-65.
  3. Nagao T, Hase T, Tokimitsu I. A green tea extract high in catechins reduces body fat and cardiovascular risks in humans. Obesity (Silver Spring). 2007Jun;15(6):1473-83.
  4. Huang L-H, Liu C-Y, Wang L-Y, et al. Effects of green tea extract on overweight and obese women with high levels of low density-lipoprotein-cholesterol (LDL-C): a randomized, double-blind, and cross-over placebo-controlled clinical trial. BMC Complementary and Alternative Medicine. 2018 Nov 6;18(1):294.

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Changes in T Cell Populations that Characterize the Progression of Immunosenescence

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Immunosenescence is the name give to the age-related decline in effectiveness of the immune system. Some authors consider this to be distinct from inflammaging, the growth in chronic inflammation due to overactivation of the immune system in response to molecular damage and the presence of senescent cells, while others consider that chronic inflammation to be an aspect of immunosenescence. In today’s open access paper, researchers review immunosenescence from the perspective of the adaptive immune system, here meaning detrimental changes in T cell populations. The contributing causes of these changes are given as (a) the atrophy of the thymus, (b) a growing bias towards production of myeloid rather than lymphoid cells in the bone marrow, and (c) the burden of persistent infection, particularly cytomegalovirus.

The progressive age-related atrophy of the thymus, known as thymic involution, may be the most important of these issues. Thymocytes created in the bone marrow migrate to the thymus, where they mature into T cells. As active thymic tissue is replaced with fat, the supply of new T cells diminishes. While the overall number of T cells remains much the same throughout life, these cells become increasingly dysfunctional due to a lack of replacements. Growing numbers of T cells in the old are senescent or exhausted, or uselessly specialized in large numbers to fight persistent pathogens such as cytomegalovirus. Ever fewer naive T cells capable of tackling new threats remain, and immune capability declines.

The importance of the thymus to immune aging is why, over the years, many research projects have sought to regrow and restore the thymus. Unfortunately none of these have yet resulted in reliable approaches in humans. Delivery of recombinant KGF was perhaps the most promising, given that it works very well to regrow the thymus in aged mice and non-human primates. The only human trial failed miserably, however, and no-one seems much interested in looking further into why this was the case. At the present time the closest approach to clinical application may that of Lygenesis: grow thymic tissue organoids and implant them into lymph nodes. I’m of the belief that upregulating FOXN1, a master regulator of thymic growth and function, is probably the best option, however. There is a long history of successfully achieving thymic regrowth via this method in mice, and the regulatory biochemistry appears to be the same in other mammalian species.

Immunosenescence: participation of T lymphocytes and myeloid-derived suppressor cells in aging-related immune response changes

Immunosenescence was initially defined as a group of changes that occur in the immune response during the aging process. The reason for that is the immune system was believed to collapse with the aging process, considering the increased susceptibility of these individuals to infectious diseases and developing cancer, reduced production of antibodies against specific antigens, increase in autoantibodies, decrease in T-lymphocyte proliferation, in addition to thymic involution. However, immunosenescence is currently defined by some researchers as remodeling of the immune system, suggesting plasticity of the immune system in the aging process. According to these researchers, the aging process does not necessarily bring an inevitable decline of immune functions; what happens is a rearrangement or an adaptation of the immune system to adjust the body that has been exposed to different pathogens throughout life. Depending on how successful that rearrangement or adaptation is, senior individuals can reach longevity with quality of life or, conversely, develop chronic diseases (comorbidities) and/or be often hospitalized due to severe infections.

This adaptation of the immune system brought by aging seems to result in reduced number and repertoire of T cells due to thymic involution, accumulation of memory T cells from chronic infections, homeostatic proliferation compensating for the number of naïve T cells, decreased proliferation capacity of T cells against stimuli, T cell replicative senescence and inflammaging, besides accumulation of myeloid-derived suppressor cells (MDSC).

As we get older, during hematopoiesis in the bone marrow, the myeloid lineage tends to increase, which can favor the accumulation of MDSC. These cells are able to suppress T cells proliferation and function, and produce pro-inflammatory cytokines. Moreover, there is thymus involution and replacement of thymic tissue by adipose tissue. Hence, there is reduced T cell receptor (TCR) variability and release of naïve T cells. The decreased thymic release of naïve cells, together with the immune response against infections throughout life, lead to the accumulation of memory T cells. In elderly individuals, both naïve and memory T cells can be maintained thanks to homeostatic proliferation, which shortens the telomeres of these cells, resulting in replicative senescence of T cells that produce pro-inflammatory cytokines, and promote inflammaging. The shortening of telomeres also decreases the proliferation capacity of T cells, which will produce less interleukin-2, further decreasing the proliferation of these cells.

Considering T cells are essential for the adequate response against pathogens and neoplasms, and for protection after vaccination, it seems reasonable that changes in T cells quantity, phenotype, and function play an important role in immunosenescence. By understanding each of the mechanisms originated by remodeling of the immune system brought by aging, we could use the cells addressed in the present study (T cells and MDSC) as early and minimally invasive biomarkers for aging-related diseases. The aim is to minimize the limitations of immunosenescence and ensure better treatment for the vulnerable elderly population.

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Another Cholesterol-Lowering Variant that Reduces Heart Disease Risk, but This One Has Unfortunate Side Effects

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In recent years, researchers have discovered a number of human gene variants or mutations that significantly lower blood cholesterol, and this also the risk of heart disease, such as DSCAML1, ANGPTL4, and ASGR1. Why does this work? Oxidized cholesterol contributes to the development of atherosclerosis with advancing age, by causing macrophages to falter in their work of removing cholesterol from blood vessel walls, become inflammatory, transform into foam cells, and die, leaving debris that grows the lesions the cells are trying to repair. Reducing overall cholesterol works because it reduces oxidized cholesterol as well.

Yet this business of reducing blood cholesterol is unfortunately far from the most efficient way to tackle atherosclerosis. It can only slow it down, and not produce significant reversal of existing fatty lesions in blood vessel walls. Nonetheless, when lowered cholesterol levels are in place for the entire lifespan rather than just as a result of statin drugs in later life, and there is a considerable prevention effect, then effect sizes can be quite large. Sadly, the mutation in APOB noted here has unpleasant side-effects that make this gene and its protein a less desirable target for therapy than the others mentioned above.

A new study finds that protein-truncating variants in the apolipoprotein B (APOB) gene are linked to lower triglyceride and LDL cholesterol levels, and lower the risk of coronary heart disease by 72 percent. Protein-truncating variants in the APOB gene are among the causes of a disorder called familial hypobetalipoproteinemia (FHBL), which causes a person’s body to produce less low-density lipoproteins (LDL) and triglyceride-rich lipoproteins. People with FHBL generally have very low LDL cholesterol, but are at high risk of fatty liver disease.

“An approved drug, Mipomersen, mimics the effects of having one of these variants in APOB, but due to the risk of fatty liver disease, clinical trials for cardiovascular outcomes won’t be done. Using genetics, we provided evidence that targeting this gene could reduce the risk of coronary heart disease.”

The researchers sequenced the APOB gene in members of 29 Japanese families with FHBL. Eight of the Japanese families had protein-truncating variants in APOB, and individuals with one of those variants had LDL cholesterol levels 55 mg/DL lower and triglyceride levels 53 percent lower than individuals who did not have an APOB variant. The researchers also sequenced the APOB gene in 57,973 participants of a dozen coronary heart disease case-control studies of people with African, European, and South Asian ancestries, 18,442 of whom had early-onset coronary heart disease. Again, they found that people with these APOB gene variants had lower LDL cholesterol and triglyceride levels. Only 0.038 percent of the people with coronary heart disease carried an APOB variant, while 0.092 percent of those without coronary heart disease did, indicating that carrying gene variants in APOB reduces the risk of coronary heart disease.


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Cellular Senescence in the Development of Cataracts

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The ability to selectively destroy senescent cells through the use of senolytic therapies doesn’t make greater understanding of the biochemistry of senescent cells irrelevant, but it does mean that we don’t have to wait around for that greater understanding to arrive in order for the development of therapies to get started. Destroy the bad cells now, benefit the patients now, and let the ongoing research proceed at its own pace. The open access paper here is an example of that ongoing research, an exploration of the proteins that might be important in cellular senescence in cataracts, a prominent cause of age-related blindness. Regardless of the outcome here, senolytic therapies should be under development to treat cataracts now, not later.

Senescence is a leading cause of age-related cataract (ARC). The current study indicated that the senescence-associated protein, p53, total laminin (LM), LMα4, and transforming growth factor-beta1 (TGF-β1) in the cataractous anterior lens capsules (ALCs) increase with the grades of ARC. In cataractous ALCs, patient age, total LM, LMα4, TGF-β1, were all positively correlated with p53.

In lens epithelial cell senescence models, matrix metalloproteinase-9 (MMP-9) alleviated senescence by decreasing the expression of total LM and LMα4; TGF-β1 induced senescence by increasing the expression of total LM and LMα4. Furthermore, MMP-9 silencing increased p-p38 and LMα4 expression; anti-LMα4 globular domain antibody alleviated senescence by decreasing the expression of p-p38 and LMα4; pharmacological inhibition of p38 MAPK signaling alleviated senescence by decreasing the expression of LMα4. Finally, in cataractous ALCs, positive correlations were found between LMα4 and total LM, as well as between LMα4 and TGF-β1.

Taken together, our results implied that the elevated LMα4, which was possibly caused by the decreased MMP-9, increased TGF-β1 and activated p38 MAPK signaling during senescence, leading to the development of ARC. LMα4 and its regulatory factors show potential as targets for drug development for prevention and treatment of ARC.


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Cognitive Benefits of Magnesium L-Threonate

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Described as a patented compound with the ability to enhance working memory, short- and long-term memory and learning in animal studies, magnesium L-threonate (shortened to MgT and pronounced “Mag T”) was developed by scientists at the Massachusetts Institute of Technology in 2010.

The animal study that first introduced MgT, published in Neuron in 2010,1 noted its ability to rapidly absorb into the brain, which structurally reversed specific aspects of brain aging by increasing the number of “functional presynaptic release sites while it reduced their release probability.”2

Magnesium is already recognized as a mineral required by your body for more than 300 crucial biological functions, such as contracting your muscles, maintaining your heartbeat, creating energy and activating nerves to send and receive messages.

However, with all its importance to your bodily functions, a large percentage of the U.S. population is deficient in magnesium, with about half not getting the recommended amounts: 310 to 320 milligrams (mg) for women and 400 to 420 mg for men.3 Presumed deficiencies vary depending on your health status and age; for example, having heart disease and being elderly increase the risk for being deficient in magnesium, one analysis found.4

But still, no matter the age, it’s apparent that magnesium deficiency is a genuine health concern worldwide. In fact, in 2006 a French study of 2,373 subjects aged 4 to 82 concluded that 71.7% of men and 82.5% of women weren’t getting adequate amounts of magnesium.5

People with low magnesium levels are at risk for a number of serious disorders, including cardiovascular disease, high blood pressure, high blood sugar and other signs of metabolic syndrome, as well as osteoporosis.6

A study published in the Journal of Alzheimer’s Disease in 20167 notes MgT’s benefits in the areas of anxiety, sleep disorders and cognitive dysfunction in human adults. The randomized, double-blind, placebo-controlled, clinical trial took place in three separate institutions, and involved participants between the ages of 50 and 70 with reported episodes of memory problems, sleep disorders and anxiety.

In short, the study found brain atrophy is a natural part of aging, but supplementation with magnesium L-threonate, aka MMFS-01, for 12 weeks improved and even reversed symptoms in the study group:

“With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo. Cognitive fluctuation was also reduced.

The study population had more severe executive function deficits than age-matched controls from normative data and MMFS-01 treatment nearly restored their impaired executive function, demonstrating that MMFS-01 may be clinically significant … The current study demonstrates the potential of MMFS-01 for treating cognitive impairment in older adults.”

Scientists Double Down on Reversing Brain Aging

To come to this conclusion, this study conducted baseline cognitive testing, with the first follow-up testing six weeks later. Then, for 12 weeks, study subjects were randomly dosed daily with either placebos or 1,500 to 2,000 mg of MgT, depending on body weight, as cognitive tests were repeated at six-week and 12-week intervals in the areas of:

  • Executive function
  • Working memory
  • Attention
  • Episodic memory (ability to recall fleeting events)

Significantly, the most “startling” finding is that not only does MgT enhance performance on individual cognitive tests in older adults with cognitive impairment, but it serves to reverse brain aging by more than nine years.8 The study’s findings revealed four significant results from MgT use:

  1. Improved body magnesium status — After 12 weeks, two things were noted in the treated group: They exhibited significantly increased red blood-cell magnesium concentration, indicating high circulating levels of magnesium in the body; and significant urinary output of magnesium, showing that large amounts of magnesium were absorbed.
  2. Improved cognitive abilities — Visual attention and task switching revealed (in some cases as early as six weeks) increases in performance speed for executive function and cognitive processing. Notably, overall composite scores rose steeply compared with baseline scores and with placebo recipients at Weeks 6 and 12.
  3. Reduced fluctuation in cognitive ability — Cognitive functions that are worse some days than others is one sign that mild cognitive impairment may be developing.9,10 Those on the placebo showed notable fluctuation in their cognitive scores, while the MgT group reflected mostly positive changes.
  4. Reversed clinical measures of brain aging — Perhaps the most significant finding, which explains how MgT can “turn back time” in aging brains.

MgT and the Blood-Brain Barrier

MgT boosts the magnesium levels in your brain when taken orally due to its ability to cross the blood-brain barrier. Once it’s in your brain, it increases the density of synapses, the communication connections between brain cells. What’s more, MgT increases this function in precisely the places needed.11,12,13

The importance of getting it to your brain shows why it isn’t as simple as adding magnesium to your diet, as MgT works differently than typical magnesium, which doesn’t reach the brain to change the factors of brain aging.14

Even raising blood magnesium levels by 300% (known as “induced hypermagnesemia”) doesn’t change cerebrospinal fluid levels by more than 19%.15 An all-encompassing study showing the complex regulatory functions of the blood-brain barrier notes:

“The environment exerts profound effects on the brain. A large body of evidence shows that brain plasticity is strongly affected by exposure to stimulating environments, with beneficial consequences throughout the entire life span.”16

One reason these discoveries were deemed critical is because there’s a connection between a loss of synaptic density, brain shrinkage and subsequent cognitive decline, the study authors said.

Understanding How MgT Rejuvenates Aging Brains

According to researchers, your brain doesn’t age at the same rate as the rest of your body. For instance, a 60-year-old can have a brain that essentially functions like that of someone a decade older. How that varies is measurable via performance test scores as well as physiological parameters.17,18,19 It can also happen in cases of traumatic brain injury.20

The MMFS-01 study shows an average chronological age of 57.8 years in their study participants. However, their cognitive function averaged 68.3 years of age — about a 10-year difference.

But supplementing with MgT made a dynamic difference: The subjects’ collective brain age decreased from 69.6 at the start of the study to just 60.6 in just six weeks’ time — a nine-year brain age drop. The improvements continued through all 12 weeks, with the brain age at the end averaging 9.4 years younger, which closely matched their peers with healthy brains.

The takeaway is the remarkable difference that magnesium, and more specifically, MgT, makes in regard to turning back time in people whose brain age is greater than that of their chronological age.

Studies also show how increasing concentrations of magnesium in cultured brain cells from the hippocampus (where memories are stored and retrieved) boosts both synaptic density and brain plasticity.21,22 The reasons this is important are twofold:

  • Synaptic density isn’t just the measure of the structural integrity of brain synapses, but evidence suggests that greater synaptic density results in more efficient cognitive processing.23
  • Plasticity is a measure of the speed at which synaptic connections can change with new stimuli — it’s essentially learning at the cellular level.24,25,26,27

Sleep Factors and Anxiety Observed in Cognitive Decline

Researchers cited a number of earlier studies exploring factors contributing to cognitive decline. Sleep loss28 and anxiety disorders29 with perceived memory loss. Not surprisingly, people with this particular set of conditions are more likely to develop Alzheimer’s, as the following studies can attest.

In a review published in 2013, researchers from several hospitals and research centers in St. Louis reported that symptoms of sleep disorders, anxiety and disrupted circadian rhythms are common in patients with Alzheimer’s disease. In their study objective, the authors wrote:

“Recent animal studies suggest a bidirectional relationship between sleep and amyloid-β (Aβ), a key molecule involved in AD (Alzheimer’s) pathogenesis. This study tested whether Aβ deposition in preclinical AD, prior to the appearance of cognitive impairment, is associated with changes in quality or quantity of sleep.”30

The upshot was that amyloid deposition was associated with an inferior quality of sleep, specifically worse sleep efficiency (the percentage of time in bed spent actually sleeping) in comparison with those without amyloid deposition, although sleep time was similar in both groups. Significantly, “Frequent napping was associated with amyloid deposition.”31

In 2007, scientists in Sweden followed 185 people for three years with no cognitive impairment along with another 47 people with depressive symptoms related to mood, motivation and anxiety. Interestingly, the scientists observed, “The predictive validity of mild cognitive impairment for identifying future Alzheimer disease cases is improved in the presence of anxiety symptoms.”32

Another 2013 study33 as a collaboration between researchers in California observed that aging is associated with regional brain atrophy, reduced slow wave activity during non-REM sleep and impaired long-term retention of episodic memories. The researchers found that age-related gray-matter atrophy was linked to sleep disorders and impaired long-term memory.

What Does Calcium Have to Do With Magnesium?

There are a few little-known but important factors regarding magnesium. One is that like other minerals, your body doesn’t produce it, so it must be derived from an outside source. Second, magnesium works hand in hand with calcium, and the optimal ratio between magnesium and calcium is 1-to-1.

However, doctors have mistakenly pushed women in particular to concentrate on their calcium intake to avoid problems with osteoporosis. With insufficient amounts of magnesium, your heart can’t function properly. When the balance between the two favors calcium, especially to the 2-to-1 ratio promoted by doctors over the past 30 years, it can result in a heart attack.

In one study,34 high incidences of hip fractures in Norway were thought to be a result of an imbalance between the concentration of calcium and magnesium in municipal drinking water. In fact, 5,472 men and 13,604 women aged 50 to 85 years suffered hip fractures, which, after an investigation, researchers concluded that increasing magnesium may protect against them.

In addition, keeping your vitamin K2 and vitamin D intake on par with magnesium and calcium is also important. The four work together. For instance, people whose magnesium intake was relatively high were shown in one study35 to be less likely to have a vitamin D deficiency, compared with people with an inadequate magnesium intake.

If you opt for a magnesium supplement, note that there are several different forms. Additionally, one way to get it is through taking regular Epsom salt baths or foot baths. This form of magnesium, magnesium sulfate, absorbs into your skin to raise your levels.

Essentially, since you get only one brain to last your entire life, scientists believe supplementing with MgT appears to be imperative for anyone wanting to preserve brain function, and even recover some function that was lost.

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New Study Shows Skullcap Herb Repairs Brain Injury

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The skullcap herb, not to be confused with the deadly autumn skullcap mushroom,1 comes in two varieties: the American skullcap (Scutellaria lateriflora) and Chinese skullcap (Scutellaria baicalensis).2 Although they come from the same family and have medical uses, they are not interchangeable.

The American skullcap is found in North America but is also grown in Europe in other areas of the world. Many of the studies done on skullcap have used Chinese skullcap, native to China and parts of Russia. It has been used in traditional Chinese medicine (TCM) for the treatment of infections, headaches, inflammation and allergies.3

The American skullcap gets its name from the cap-like appearance of the purple or blue flowers gracing the heavily branched plant.4 The plant grows to 4 feet in height and may be found growing wild in the woods. The Chinese skullcap flowers on a single stem growing 1 foot high.5 Both herbs are available as a powdered extract, and the American skullcap may be found in liquid form.

One flavonoid compound — scutellarin — is found in the plant genus Scutellaria and Erigeron.6 An extract from the herb Erigeron breviscapus — breviscapine — has been used in TCM and in the treatment of a variety of diseases. Breviscapine contains high amounts of scutellarin, and scutellarin is also found in the American and Chinese skullcap herbs.

Flavonoid in Skullcap Has Neuroprotective Effect After Brain Injury

Breviscapine is an extract of flavonoids from the herb Erigeron breviscapus, which contains 85% of scutellarin also found in Scutellaria, or skullcap.7 A recent study published in the Journal of Cellular Biochemistry8 investigated the neuroprotective effects of breviscapine after traumatic brain injury (TBI).

Researchers induced a closed diffuse TBI in rats and then injected breviscapine into their abdomen 30 minutes later. The researchers performed neurological scores to measure behavioral outcomes as an indication of neurological damage. Histopathological tissue sections of the rat’s brains were subsequently used to evaluate cellular damage.

The researchers found nuclear factor erythroid 2–related factor 2 (Nrf2) and downstream proteins in the brain tissue. They concluded breviscapine could alleviate or reduce cell death following a TBI and improve neurobehavioral functions through upregulation of Nrf2.9

Nrf2 has been described as the “master regulator of oxidative responses.”10 It is recognized as one of the major mediators in the resolution of inflammation and has been found to induce the expression of antioxidants that are crucial in the initiation of healing.

The Journal of Cellular Biochemistry study11 concluded that the downstream proteins12 (including HO-1 and NQO-1) detected in the histological tissue sections indicated upregulation of Nrf2. Expression of Nrf2 and the interaction with signaling pathways may facilitate development of therapeutic approaches to help reduce chronic inflammatory diseases.

Nrf2 is also a regulator of cellular resistance to oxidants,13 as part of a complex antioxidant defense system. It may also control the expression of genes involved in detoxification and elimination of reactive oxidants.14

Protective Effect of Scutellarin Found in Heart, Liver and Kidney Studies

The protective effect breviscapine initiates in the NRF2 pathway against cellular apoptosis and oxidative stress following injury may also play a role in the positive effects it plays in the heart, liver and kidneys. Memorial Sloan-Kettering Cancer Center15 reports scutellarin has purported uses in atherosclerosis, inflammation, epilepsy and hepatitis.

In a study published in the Journal of Cardiovascular Pharmacology,16 researchers used Sprague-Dawley rats to induce focal cerebral ischemia and heart ischemia followed by treatment with breviscapine or scutellarin. Their results found the protective effects of scutellarin in both the heart and brain were better than the mixture in breviscapine.

An article in the Frontiers in Pharmacology17 reported several clinical studies found breviscapine may be used in conjunction with medication for a variety of cardiovascular diseases, including myocardial infarction, atrial fibrillation, chronic heart failure and pulmonary heart disease.

The active antioxidant effect also reduces liver ischemia-reperfusion injury. In a study18 of 40 rats, histopathologic analysis was performed 24 hours after reperfusion. Researchers found breviscapine reduced injury by inhibiting liver oxidative stress. During an ischemic event, cellular death begins. When blood supply is restored, additional damage may occur from free radical activity.19

Several other studies have described a renal protective effect of breviscapine in animal20 and human studies. In one meta-analysis,21 researchers found breviscapine injections had a therapeutic effect in those with diabetic nephropathy, including a renal protective effect.

Another22 found breviscapine injections, in combination with antihypertensive drugs, improved clinical outcomes in those treated for hypertensive nephropathy and could serve as a renal protective strategy for patients.

Additional Health Benefits From Scutellarin

In a letter to the editor in the Journal of Cellular and Molecular Medicine,23 researchers describe the use of breviscapine in an animal study demonstrating its effect against pulmonary embolism. They concluded there was a reduction in inflammation in the lung tissues, which facilitated reduction in vasoconstriction.

Scutellarin has a traditional use as a potent antiplatelet agent. In one study,24 using mice with induced endometriosis, researchers concluded scutellarin was an efficient treatment by suppressing platelet aggregation and inhibiting proliferation, fibrogenesis and angiogenesis. These factors resulted in a reduction in lesion size and an improvement in pain in the mice.

American skullcap is also a traditional herbal medicine used in the treatment of stress and anxiety.25 In one placebo-controlled, double-blind, crossover study26 using 43 healthy participants, researchers found American skullcap “significantly enhanced global mood without a reduction in energy or cognition.”

The effects of scutellarin have also been considered a promising candidate for the development of therapeutic drugs against transmissible spongiform encephalopathies (TSEs) leading to the loss of neurons and synaptic functions.27 In humans, TSEs include neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.

Additionally, Chinese skullcap has antihistamine properties, traditionally used to treat allergic rhinitis, asthma and eczema.28 Scutellarin has also demonstrated in vitro antibacterial and in vivo anti-inflammatory properties.29

Researchers found the anti-inflammatory effects of scutellarin to be helpful as an additional treatment with bleomycin, a broad-spectrum antitumor drug. The study30 was aimed at investigating a combined treatment protocol using in vivo and in vitro experiments in animals.

The results suggested scutellarin enhanced the anticancer effect of bleomycin, and at the same time reduced the drug’s side effect of pulmonary fibrosis.31 The herb also has been used in TCM for the treatment of:32,33,34




High blood pressure

Respiratory infections






Liver protection





Potential Side Effects of Skullcap

While use of herbs is a traditional approach to strengthen the immune system and treat disease, some may trigger side effects and interact with supplements or medications. Penn State Milton S Hershey Medical Center35 warns that the American skullcap herb has been contaminated in the past and so should be obtained from a reliable source.

Those with diabetes should take Chinese skullcap only under a doctor’s supervision, as it may reduce blood sugar levels and raise the risk of hypoglycemia. Chinese skullcap may exacerbate stomach or spleen problems and should not be used during pregnancy or breastfeeding.36

American skullcap may induce mental confusion, irregular heartbeat and seizures when taken in high doses. Both also have a sedative effect and may increase the effect from anticonvulsants, barbiturates, benzodiazepines, tricyclic antidepressants, alcohol and drugs used to treat insomnia.37

The Flowers Are Beautiful and the Tea Promotes Relaxation and Other Health Benefits

While skullcap is available in powder and tincture form, you may also enjoy a hot cup of skullcap tea in the evening. Take care if you drink it during the day as it has a sedative effect. Driving or operating machinery after drinking it may be dangerous.

You may get two servings of tea from 1 tablespoon of high-quality skullcap herb and 2 cups of boiling water.38 Steep the tea in a teapot for 10 minutes and then, if you prefer, sweeten with raw honey, Luo han or stevia.

American skullcap typically blooms between May and August in zones 4 to 839 and prefers partial shade to full sun, while Chinese skullcap enjoys full sun and dry sandy soil. Skullcap may easily be grown from seed as they germinate at a naturally high rate, especially when stratified.40

In this process,41 you treat the seeds to simulate germination. Cold stratification is easily done in the refrigerator. Mix a quarter cup of sand in a mixing bowl and add water until it can form ball. Add your desired seed amount to the sand, mix it thoroughly and place it in a bag in the refrigerator for one week.

The seeds can be sown indoors before the first frost or outdoors once the threat of frost is gone. Ensure the soil is moist, but well-drained. You may also propagate by dividing roots or cuttings and allowing them to spread. Skullcap can be harvested once the flowers are in full bloom using a pair of scissors or shears to retrieve the flowers and leaves.

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VCAM1 Levels Correlate with Parkinson's Disease Severity

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Levels of VCAM1 in the bloodstream increase with age, and it appears to be an important signal molecule in at least the brain. Its expression is upregulated by inflammatory cytokines, and so is a marker of inflammatory disease. Chronic inflammation of course increases with age. Researchers have shown that blocking VCAM1 can prevent suppression of neurogenesis due to delivery of old blood plasma into young mice, which is an interesting result, as one might not expect detrimental reactions to inflammatory signaling to have such a narrow bottleneck of regulation. Would a method of interfering with VCAM1 assist in tissue maintenance and cognitive function in older individuals? That remains to be determined with any certainty. The work here showing a correlation between VCAM1 and severity of Parkinson’s disease, a neurodegenerative condition, reinforces the point that high levels of VCAM1 are undesirable.

There is increasing evidence that Parkinson’s disease (PD) pathology is accompanied by ongoing inflammatory processess. This neuroinflammatory component is particularly relevant for better understanding disease progression accordingly developing disease-modifying therapies. Therefore, the present study explored dysregulated inflammatory profiles in the peripheral blood cells and plasma of PD patients within the context of established clinical indicators. We performed a screening of selected cell-surface chemokine receptors and adhesion molecules in peripheral blood mononuclear cells (PBMCs) from PD patients and age-matched healthy controls in a flow cytometry-based assay. ELISA was used to quantify VCAM1 levels in the plasma of PD patients.

The present data illustrate the role soluble VCAM1 (sVCAM1) levels may play in PD pathology. The levels of sVCAM1 observed here were even higher than those reported for patients with rheumatoid arthritis, multiple sclerosis, and neuromyelitis optica. Although substantial evidence exists for the association between increased sVCAM1 and age and cognitive impairment, the use of age-matched healthy donors in this study has illustrated that the increase observed in PD is independent of physiological aging. Furthermore, sVCAM1 correlated with both disease stage and the motor aspects of daily living.

Whether elevated sVCAM1 levels actively drive disease progression in PD or are a consequence of it remains to be fully understood. Of note, VCAM1 has already been implicated to be a potential mediator of PD pathogenesis. Thus, whether targeting the VCAM1-VLA4-axis is a viable therapeutic avenue remains to be established. Indeed, promising evidence for the therapeutic potential of the VCAM1-VLA4 axis in age-related pathologies of the central nervous system already exists; it has been shown that blocking VCAM1 slows down normal brain aging, induces neurogenesis, and ameliorates neuroinflammation. Our chemotaxis assay revealed diminished lymphocytic migration in PD patients which may be indicative of compromised cellular adherence and infiltration of endothelial barriers. Therefore, additional investigations and in vivo studies addressing both the expression and functional state of VCAM1 on brain endothelial cells are necessary.


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Impaired Insulin Signaling and Chronic Inflammation in the Alzheimer's Brain

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In past years, there has been considerable discussion of Alzheimer’s disease as a type 3 diabetes. This is by no means a formal designation, but enough papers have put forward the concept that when a new version of diabetes was in fact discovered not so long ago, it had to be designated type 4. Why call Alzheimer’s a form of diabetes? Because dysregulation of insulin metabolism appears to be a feature of the condition. In the paper here, these issues with insulin signaling are linked to the generation of chronic inflammation. This makes a great deal of sense in the broader context of what is known of Alzheimer’s disease, as dysregulation of immune cells in the brain, and rising levels of inflammatory signaling, are thought to arise from the presence of amyloid-β and in turn generate tau aggregates and severe pathology in the brain. In effect, inflammation bridges the early, mild stages of the condition and the later severe stages and their very different biochemistries.

Recently, type 2 diabetes mellitus (T2DM) has been identified as a risk factor for Alzheimer’s disease (AD). Epidemiological studies of patient data sets have found a clear correlation between T2DM and the risk of developing AD or other neurodegenerative disorders. In one study, 85% of AD patients had diabetes or showed increased fasting glucose levels, compared to 42% in age-matched controls. In longitudinal studies of cohorts of people, it was found that glucose intolerance was a good predictor for the development of dementia later in life.

When analyzing the brain tissue of AD patients, it was observed that insulin signaling was much desensitized, even in AD patients that did not have T2DM. One study found that the levels of insulin, IGF-1, and IGF-II were much reduced in brain tissue. In addition, levels of the insulin receptor, the insulin-receptor associated PI3-kinase, and activated Akt/PKB kinase were much reduced. A second study found increased levels of IGF-1 receptors and the localization of insulin receptors within cells rather than on the cell surface where they could function.

Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common – they induce a chronic inflammation response in the brain. Insulin reduces the chronic inflammation response by inhibiting secondary cell signaling induced by pro-inflammatory cytokines. A desensitization of insulin signaling enhances the inflammation response and the desensitization observed in T2DM, therefore, not only compromises growth factor signaling, and energy utilization in the brain, but also facilitates the chronic inflammation response.


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Fight Aging! Newsletter, May 20th 2019

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Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn’t work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

This content is published under the Creative Commons Attribution 4.0 International License. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • The Goal of Fixing the Power Plants of the Cell
  • Anethole Trithione is a Mitochondrial ROS Blocker
  • Towards Restoration of Neural Stem Cell Function in the Old
  • Poor Sense of Smell Correlates with Increased Mortality in Older Individuals
  • Is α-synuclein, Like Tau, Driven to Aggregate by the Activities of Inflammatory Microglia?
  • Unity Biotechnology’s Locally Administered Senolytic Trials
  • MicroRNA-199 Produces Significant Heart Regeneration in Pigs
  • Evidence for the Mutation Accumulation Hypothesis of the Origin of Aging
  • An Analysis of Six Decades of Change in the Variability of Human Life Span
  • Mitochondrial Dysfunction as a Contributing Cause of Osteoporosis
  • Rejuvenate Bio to Launch a Gene Therapy Trial for Heart Failure in Dogs
  • Aging, Metabolic Rate, and the Differences Between Birds and Mammals
  • The DNA Damage Response Falters in Old Stem Cells
  • Mitochondrial Function and the Association Between Health and Intelligence
  • Nematodes are Probably Not Useful Models of Mitochondrial Aging

The Goal of Fixing the Power Plants of the Cell

The power plants of the cell are, of course, the mitochondria. Every cell has a herd of hundreds of mitochondria roaming its cytoplasm, working to generate ever more copies of the chemical energy store molecule adenosine triphosphate that is used power cellular processes. Mitochondria are the distant descendants of ancient symbiotic bacteria. Like bacteria they replicate by division, but also tend to fuse together and promiscuously pass around component parts. Since the original symbiosis, mitochondria have evolved into component parts of the cell. They have their own remnant DNA, but much of the original genome has migrated into the cell nucleus over evolutionary time. Further, mitochondria are monitored and recycled when worn or damaged by the cell’s autophagic mechanisms, a constant process of quality control.

Mitochondrial function declines with age. In a minority of cells, mitochondrial DNA becomes damaged in ways that allow mutant mitochondria to outcompete their functional counterparts in the herd. The cell becomes pathological, exporting harmful oxidative molecules into the surrounding tissue. This contributes to conditions such as atherosclerosis via the creation of oxidized lipids that cause macrophages to become harmful, inflammatory foam cells. In the majority of cells, mitochondria undergo a form of general malaise, becoming structurally altered and less effective in their primary role of providing energy for the cell. This may be due to a failure of quality control mechanisms, which in turn may be due to declining mitochondrial fission, but the deeper roots of these issues are unclear.

It is generally acknowledged in the research community that at least slowing and preferably turning back the course of mitochondrial dysfunction in aging is a good idea. Mitochondrial dysfunction is quite clearly implicated in many age-related diseases, particularly neurodegenerative conditions. It may underlie more subtle and pervasive manifestations of aging such as declining stem cell function that leads to reduced tissue maintenance throughout the body, as well as the many downstream issues resulting from that. I have to say that, despite this consensus, all too little of the research community is working on means of addressing mitochondrial aging that have the potential for true rejuvenation of function.

Outside of the SENS rejuvenation research programs, the mainstream of the scientific community looks toward calorie restriction mimetics and other means of tinkering with mitochondrial function without addressing the root causes of decline. Increasing the amount of NAD+ in circulation in cells, for example, is presently popular. This will produce benefits in older individuals, and the initial trials seem promising in that respect, but it doesn’t solve the underlying problems. Thus this approach cannot achieve more than modest improvements in health and longevity, as those underlying problems remain, to gnaw away at the function of cells and tissues in myriad ways. The open access paper here is an example of this sort of focus, in that it does not look beyond ways to alter mitochondrial metabolism, perhaps making mitochondria a little more active or a little more resilient in the face of underlying damage. We can and must do better than this.

Negative Conditioning of Mitochondrial Dysfunction in Age-related Neurodegenerative Diseases

In a bid to unravel how and why aging occurs, a plethora of different theories of aging have surfaced over the decades. The free radical theory, which was first proposed in 1957 is one of the most well-known and longstanding theories of aging. The free radical theory suggests that mitochondria play a crucial role in aging, as they are the main source of reactive oxygen species (ROS), leading to increased mitochondrial DNA (mtDNA) mutations. Such aging-associated mtDNA mutations thus perturb mitochondrial function resulting in pathological conditions. Mitochondria, the molecular batteries of the cell, play a crucial role in regulating the energy of the cells by producing adenosine triphosphate (ATP) through oxidative phosphorylation. Their prominent role in cell homeostasis in almost all tissues thus explains its postulated widespread effects on aging.

In light of the wide-ranging effects of aging and the associated neurodegenerative diseases on mitochondrial dysfunction, negative conditioning thus surfaces as a solution to tackle the problem. Despite the fact that the mechanism of action of neurodegenerative conditions on mitochondrial dysfunction remains to be elucidated, the possible mechanisms and the potential key molecules involved have been narrowed, and could lead to new avenues for therapeutic intervention to improve mitochondrial quality and function.

Molecular evidence of mitochondrial dysfunctions opens up possibilities for targeting specific molecules or complexes for biochemical or pharmacological therapeutic interventions. Given the neuroprotective function conferred by Parkin and PINK1, their deficiencies could be targeted to restore mitochondrial function in Parkinson’s disease patients. For instance, nilotinib, a c-Abl tyrosine kinase inhibitor that is able to cross the blood brain barrier, can be used to increase Parkin levels. Parkin recruitment could also be increased by upregulating mutant PINK1 activity via kinetin triphosphate, an ATP analogue. Rapamycin is well-known to specifically inhibit the mammalian target of rapamycin (mTOR), which is a master regulator of growth and metabolism. Experimental evidence has shown that rapamycin reduced mitochondrial dysfunction after cerebral ischemia and this reduction was linked to significantly upregulated mitophagy.

Recently, researchers have looked at phytochemicals, natural compounds of vegetal origin, as a potential means of therapy. This approach is perceived to be closer to ‘natural’ treatment since the compounds are consumed in the diet, occur at physiological concentrations, or are known as traditional medicine. Notably, resveratrol, curcumin, quercetin, and sulforaphane are phytochemicals with the ability to contribute to negative conditioning of mitochondrial dysfunction. They do so by altering mitochondrial function and processes.

Dietary energy restriction (DR) by daily calorie restriction (CR) or intermittent fasting (IF) has been shown to extend lifespan and health span in various animal models. In addition, both CR and IF protect against age-related cardiovascular diseases and neurodegenerative diseases. Under CR, reactive oxygen species (ROS) generation has been observed to decrease especially at the liver and heart mitochondrial complex I in several studies. Such finding sheds light on how decreasing ROS can reduce disease occurrence. In an attempt to elucidate the molecular mechanism involved, numerous hypotheses have been put forth to explain how CR reduces ROS. One such hypothesis is that lowering the inner mitochondrial membrane potential along with the associated proton leak, may lead to a reduction in ROS generation. Due to reduced plasma concentration of hormones like thyroxin (T4) and insulin by CR, loss of double bonds in the membrane phospholipids is induced, resulting in a decline in the unsaturation/saturation index in several animal models tested. Such reduction increases membrane resistance to peroxidation injury thus lowering oxidative damage.

While numerous unresolved questions persist about the mechanistic link between neurodegenerative diseases and mitochondrial dysfunction, the fact that mitochondrial dysfunction plays a crucial role in the pathogenesis is clear. Mitochondrial dysfunction is a wide-ranging phenomenon that is triggered by a cohort of molecules, often incurring damage via multiple pathways. Despite decades of research on neurodegenerative diseases, treatment options remain purely symptomatic due to the unknown etiology. Given the common role played by mitochondrial dysfunction in neurodegenerative conditions, it provides a potential avenue for effective therapeutic intervention, and hopefully a platform for early intervention.

Anethole Trithione is a Mitochondrial ROS Blocker

Mitochondria, the power plants of the cell, generate reactive oxygen species (ROS) as a side effect of the energetic operations needed to package fuel supplies used by cellular processes. While ROS are necessary signals in many physiological circumstances, such as the beneficial reaction to exercise, excessive ROS generation can be harmful. Excessive ROS generation is also observed in aging. Suppressing that excessive ROS flux at its source, without affecting the beneficial signaling roles, has been demonstrated to be beneficial in disease states characterized by inflammation and high degrees of oxidative stress. It may also very modestly slow the progression of aging.

A number of mitochondrially targeted antioxidant compounds have been developed over the past fifteen years, and shown to produce at least some these benefits: MitoQ, SkQ1, SS31, and so forth. An alternative approach to delivering antioxidants to the mitochondria, to soak up ROS as they are generated, is to suppress the production of ROS. The challenge here is doing this without disrupting the normal function of mitochondria, which would of course be far more damaging than any potential realized benefit.

Regardless, a small class of mitochondrial ROS blocker compounds does exist, and here researchers show that the approved drug anethole trithione, also known as sulfarlem, and in this paper, confusingly, by the designation OP2113, is also a mitochondrial ROS blocker. It can achieve this goal without greatly altering mitochondrial function. It remains to be seen as to whether this compound can do as well as mitochondrially targeted antioxidants, should it or an improved version be further developed for this clinical use. It is worth remembering that even it it does, and can improve health to some degree, as suggested by human clinical trials, the effects on longevity will be vanishingly small in long-lived species such as our own. They are not large in flies or mice, species with a far greater plasticity of longevity.

An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

The free radical theory of aging suggests that free radical-induced damage to cellular structures is a crucial event in aging; however, clinical trials on antioxidant supplementation in various populations have not successfully demonstrated an anti-aging effect. Current explanations include the lack of selectivity of available antioxidants for the various sources of oxygen radicals and the poor distribution of antioxidants to mitochondria, which are now believed to be both the primary sources of reactive oxygen species (ROS) and primary targets of ROS-induced damage. Indeed, mitochondrial dysfunction that occurs due to accumulation of oxidative damage is implicated in the pathogenesis of virtually all human age-related diseases.

Given the key role of age-dependent mitochondrial deterioration in aging, there is currently a great interest in approaches to protect mitochondria from ROS-mediated damage. Mitochondria are not only a major source of ROS but also particularly susceptible to oxidative damage. Consequently, mitochondria accumulate oxidative damage with age that contribute to mitochondrial dysfunction. Cells and even organelles possess several protection pathways against this ROS-mediated damage given that local protection is fundamental to circumvent the high reactivity of ROS. Therefore, mitochondria appear as the main victims of their own ROS production, and evidence suggests that the best mitochondrial protection will be obtained from inside mitochondria.

his conclusion has driven several potential therapeutic strategies to improve mitochondrial function in aging and pathologies. Antioxidants designed for accumulation by mitochondria in vivo have been developed and are currently being thoroughly tested for mitochondrial protection. The growing interest in ROS production associated with diseases has elicited numerous clinical trials that have also demonstrated that uncontained ROS reduction in cells is deleterious, and it appears that an adequate balance of ROS production is necessary for correct cell function. As a consequence, there is also a growing interest in the selective inhibition of ROS production of mitochondrial origin that would not affect cellular signalization involving either mitochondrial or cytosolic ROS production.

The molecule OP2113 (Anetholtrithion, or 5-(4-methoxyphenyl)dithiole-3-thione, CAS number 532-11-6) has been marketed in many countries and used in human therapy in certain countries including France, Germany, and China for its choleretic and sialogogic properties. Anetholtrithion also exhibits chemoprotective effects against cancer and various kinds of toxicity caused by some drugs and xenobiotics. These chemoprotective effects appear to be mainly due to its antioxidant properties. The most typical indications for which anetholtrithion is currently used include increasing salivary secretion in patients experiencing dry mouth.

However, until now, no precise mechanism of action has been described for this molecule. Considering the high lipophilicity of OP2113, which represents a promising characteristic for mitochondrial targeting, we investigated the effect of OP2113 on mitochondrial ROS/H2O2 production. Here we show that OP2113 decreases ROS/H2O2 production by isolated rat heart mitochondria. Interestingly, it does not act as an unspecific antioxidant molecule, but as a direct specific inhibitor of ROS production at complex I of the mitochondrial respiratory chain, without impairing electron transfer. This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2.

Towards Restoration of Neural Stem Cell Function in the Old

Every tissue in the body supported by its own specialized small stem cell populations. The vast majority of cells in the body, known as somatic cells, are limited in the number of times they can divide. Their telomeres shorten with each cell division, and they become senescent or self-destruct when reaching the Hayflick limit on replication, triggered by short telomeres. Stem cells have no such limitation, and use telomerase to maintain telomere length regardless of the number of divisions they undergo. They divide asymmetrically to generate daughter somatic cells with long telomeres that can replace lost somatic cells in order to maintain tissue function. This split between a small privileged cell population and a large, limited cell population most likely evolved because it greatly reduces the risk of cancer.

Unfortunately, stem cell activity declines with age, producing a slow decline of tissue function, ultimately causing disease and death. This may also be an adaptation that exists to reduce cancer risk. From a mechanistic point of view, it appears to be a reaction to rising levels of molecular damage, and the consequences of that damage, such as chronic inflammation and other forms of altered signaling between cells. While some stem cell populations are damaged and diminished in and of themselves in older individuals, such as hematopoietic stem cells, others, such as muscle stem cells, have been shown to be just as capable in old age as in youth, but much less active. The stem cells lapse into extended quiescence and cease to create daughter somatic cells.

Neural stem cells appear more akin to muscle stem cells than hematopoietic stem cells in the matter of whether or not they still exist in old individuals and are capable of activity, given the right instructions. The activity of neural stem cells is an important portion of neuroplasticity, the ability of the brain to generate new neurons that integrate into existing neural circuits or form new neural circuits. This is the basis of cognitive function and also of repair in the brain. To the degree that the supply of new neurons declines, this is a slow road to neurodegeneration. Many other issues need to be fixed in the aging brain, such as chronic inflammation, slowed drainage of cerebrospinal fluid, and the aggregation of proteins associated with neurodegenerative conditions. Nonetheless, stem cell function must be restored in some way.

Prince Charming’s kiss unlocking brain’s regenerative potential?

As we age, our brains’ stem cells ‘fall asleep’ and become harder to wake up when repairs are needed. Despite efforts to harness these cells to treat neurological damage, scientists have until recently been unsuccessful in decoding the underlying ‘sleep’ mechanism. Now, researchers studying brain chemistry in mice have revealed the ebb and flow of gene expression that may wake neural stem cells from their slumber.

The team focused their attention on protein Hes1, which is strongly expressed in the adult cells. This normally suppresses the production of other proteins such as Ascl1, small amounts of which are periodically produced by active stem cells. Monitoring the production of the two proteins over time, the team pinpointed a wave-like pattern that leads to stem cells waking up and turning into neurons in the brain. When they knocked out the genetic code needed to make Hes1, the cells started to make more Ascl1, which then activated almost all the neural stem cells.

“It is key that the same genes are responsible for both the active and quiescent states of these stem cells. Only the expression dynamics differ between the two. A better understanding of the regulatory mechanisms of these different expression dynamics could allow us to switch the dormant cells on as part of a treatment for a range of neurological disorders.”

High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain

Somatic stem/progenitor cells are active in embryonic tissues but quiescent in many adult tissues. The detailed mechanisms that regulate active versus quiescent stem cell states are largely unknown. In active neural stem cells, Hes1 expression oscillates and drives cyclic expression of the proneural gene Ascl1, which activates cell proliferation. Here, we found that in quiescent neural stem cells in the adult mouse brain, Hes1 levels are oscillatory, although the peaks and troughs are higher than those in active neural stem cells, causing Ascl1 expression to be continuously suppressed.

Inactivation of Hes1 and its related genes up-regulates Ascl1 expression and increases neurogenesis. This causes rapid depletion of neural stem cells and premature termination of neurogenesis. Conversely, sustained Hes1 expression represses Ascl1, inhibits neurogenesis, and maintains quiescent neural stem cells. In contrast, induction of Ascl1 oscillations activates neural stem cells and increases neurogenesis in the adult mouse brain. Thus, Ascl1 oscillations, which normally depend on Hes1 oscillations, regulate the active state, while high Hes1 expression and resultant Ascl1 suppression promote quiescence in neural stem cells.

Poor Sense of Smell Correlates with Increased Mortality in Older Individuals

It is quite easy to find correlations between the many varied aspects of aging. People age at different rates, largely due to differences in lifestyle choices: exercise, calorie intake, smoking, and so forth. Genetics are less of an influence. While there is tremendous interest in the genetics of aging, I have to think that this is something of a case of a hammer in search of a nail. This is an era of genetic technologies and genetic data, in which the cost of the tools has fallen so low and the scope of the capabilities has expanded so greatly that everyone is tempted to use it in every possible circumstance. Yet outside of the unlucky minority who suffer severe inherited mutations, genetic variations only become important in later life, and even then the contribution of genetics to life expectancy is much smaller than that of lifestyle choices.

Nonetheless, the point is that different people age at different rates. For any given person, however, the many aspects of aging are fairly consistent with one another – nothing races ahead in isolation. Aging is a body-wide phenomenon of multiple processes of damage accumulation that proceed in an entangled fashion, feeding one another and all contributing to systemic downstream consequences, such as chronic inflammation or vascular dysfunction. In this sort of a system, if any one organ or biological system is more aged and damaged in a given individual, then it is very likely that all of the others are as well. This works for correlations with mortality as well as specific age-related diseases or metrics.

In the research results noted below, a poor sense of smell in older individuals correlates with a significantly raised risk of mortality over a ten year horizon. For the reasons given above, this shouldn’t be terrible surprising. Loss of sense of smell is a reflection of levels of neurodegeneration, loss of function in the brain. That in turn tends to match up with loss of function elsewhere in the body, particularly in the cardiovascualar system. Failing sense of smell is further specifically associated with Alzheimer’s disease, as the olfactory system in the brain is where the condition starts. You can look at the work of Leucadia Therapeutics for evidence that Alzheimer’s disease begins in this way because clearance of cerebrospinal fluid in that part of the brain is impaired with age, leading to increased molecular waste and cellular dysfunction.

Poor Sense of Smell and Risk for Death in Older Adults

Many older adults have a poor sense of smell, which can affect their appetite, safety, and quality of life. It is also associated with increased risk for death and may be an early sign of some diseases, like Alzheimer’s disease and Parkinson’s disease. Most previous studies have studied people with a poor sense of smell for relatively short periods of time, and they did not examine whether there are differences by race or sex. We also need a better understanding of the factors that might explain the relationship between poor sense of smell and increased risk for death.

Researchers analyzed data on the members of an ongoing study that was done in 2 communities in the United States (Memphis, Tennessee, and Pittsburgh, Pennsylvania). There were 2289 adults, aged 71 to 82 years, at baseline. The participants completed a Brief Smell Identification Test (BSIT). As part of the test, they smelled 12 common odors and were asked to identify each odor from 1 of 4 options. Each correct response was given a point. Using the BSIT scores, the researchers classified the participants as having good, moderate, or poor sense of smell. Participants attended several clinical study visits, where they were examined and had cognitive tests. In these visits, patients were identified as having dementia or Parkinson’s disease, and staff measured participants’ body weights. The main end points for the study were death from any cause; death from dementia or Parkinson’s disease; and death from cardiovascular disease, cancer, or respiratory causes.

A poor sense of smell was associated with older age, male sex, black race, alcohol drinking, and smoking. It was also associated with dementia, Parkinson’s disease, and chronic kidney disease. Participants with a poor sense of smell had a nearly 50% higher risk for death at 10 years. A poor sense of smell was also associated with increased risk for death from dementia or Parkinson’s disease and death from cardiovascular disease. The investigators did some exploratory statistical analyses and found that weight loss and a history of dementia or Parkinson’s disease could explain only part of the relationship between poor sense of smell and death.

Relationship Between Poor Olfaction and Mortality Among Community-Dwelling Older Adults: A Cohort Study

To assess poor olfaction in relation to mortality in older adults and to investigate potential explanations, 2289 adults aged 71 to 82 years at baseline underwent the Brief Smell Identification Test in 1999 or 2000 (baseline). All-cause and cause-specific mortality was assessed at 3, 5, 10, and 13 years after baseline. During follow-up, 1211 participants died by year 13. Compared with participants with good olfaction, those with poor olfaction had a 46% higher cumulative risk for death at year 10 and a 30% higher risk at year 13.

However, the association was evident among participants who reported excellent to good health at baseline but not among those who reported fair to poor health. In analyses of cause-specific mortality, poor olfaction was associated with higher mortality from neurodegenerative and cardiovascular diseases. Mediation analyses showed that neurodegenerative diseases explained 22% and weight loss explained 6% of the higher 10-year mortality among participants with poor olfaction.

Is α-synuclein, Like Tau, Driven to Aggregate by the Activities of Inflammatory Microglia?

What are the important steps in the progression of neurodegenerative diseases characterized by the presence of protein aggregates? These aggregates are misfolded or otherwise altered proteins that precipitate to form solid deposits. This means α-synuclein in the case of Parkinson’s disease, or amyloid-β and tau in the cause of Alzheimer’s disease, to pick the best known examples. A growing body of evidence is pointing to dysfunction and inflammation in the immune cells known as microglia, a type of macrophage resident in the central nervous system. Like macrophages elsewhere in the body, microglia are responsible for chasing down pathogens and clearing up debris. They also participate in a range of other supporting activities that assist the function of neurons.

In Alzheimer’s disease, there is compelling evidence for microglia to be driven into an inflammatory state by the presence of amyloid-β. They act as the bridge between the mild earlier stage of the condition, in which amyloid-β accumulates, and the later stage in which tau aggregates form and neurons die. It is the chronic inflammation and dysfunction of microglia in brain tissue that drives this more severe tau pathology. Inflammatory behavior in microglia appears to involve significant numbers of senescent microglia, and researchers have shown that removing these senescent cells can turn back tau pathology in mouse models and reduce levels of neuroinflammation. Lingering senescent cells of any cell type cause harm through secreting inflammatory and other signals, the senescence-associated secretory phenotype (SASP). This actively maintains a disordered tissue environment, and we’d all benefit from its removal in old age.

Given that microglia have this role in Alzheimer’s disease, are they also causing similar issues in other neurodegenerative disease processes? Most likely yes. The article here examines the role of microglia in α-synuclein aggregation, an important part of the progression of Parkinson’s disease. This continues to add support for the idea that senolytic therapies, capable of removing senescent cells and dampening the inflammation that they cause, will prove to be a useful treatment for neurodegenerative conditions. Indeed, they should be a useful preventative treatment prior to the advent of neurodegenerative disease. Chronic inflammation drives many of the common diseases of aging, and to the extent that the causes of that inflammation can be prevented, then age-related disease – and aging itself – will be pushed back.

Do Immune Cells Promote the Spread of α-Synuclein Pathology?

How does α-synuclein pathology spread? Researchers say immune cells bear some of the blame. Certain types of inflammation in the intestine modulate α-synuclein accumulation there. In mice, experimental colitis at a young age accelerated α-synuclein pathology in the brain 18 months later, consistent with the idea that misfolded protein can travel from gut to brain. Other research implicates brain immune cells in propagation. Mutant α-synuclein oligomers that were incapable of forming fibrils still stimulated aggregation in brain. They appeared to work their mischief by firing up inflammation, suggesting that microglia somehow mediate α-synuclein spread.

First, peripheral immunity. Scientists know that intestinal infections or inflammation can pump up α-synuclein production in the gut, perhaps as part of an antimicrobial defense. This strengthened the idea that Parkinson’s disease might start in the intestine and travel from there to the brain. People who suffer from inflammatory bowel disorders are at elevated risk of Parkinson’s disease, and genetic studies have found shared risk between the two. While the links are suggestive, no one had yet shown directly that gut inflammation triggered brain pathology.

Researchers provoked colitis in 3-month-old transgenic α-synuclein mice by adding dextran sulfate sodium (DSS) to their water. This irritant caused macrophages to invade the lining of the gut wall. In response, enteric neurons lying just below the mucosa, in the submucosal plexus, began to accumulate α-synuclein. The researchers aged the mice to 12 or 21 months. At 12 months, they saw no difference between the brains of control transgenics and those that had colitis as youngsters. By 21 months, however, the colitis group had six times more α-synuclein aggregates in brainstem regions than controls did. These mice had but half as many dopaminergic neurons as controls, suggestive of neurodegeneration.

Researchers are also interested in how α-synuclein aggregates propagate within the brain. When researchers injected aggregated material into mouse brain, it was quickly cleared to undetectable levels. Then, after an incubation period, aggregates appeared and spread through brain. The leading theory holds that this occurs through templated seeding of endogenous α-synuclein by the injected aggregates. To test this idea, researchers used a mutant form of α-synuclein, V40G, that forms unstructured oligomers but is incapable of forming fibrils. In a test tube, V40G blocks fibrillization of wild-type α-synuclein as well. Thus, this form should prevent templated seeding in vivo.

The researchers injected either V40G or wild-type α-synuclein into the striata of wild-type mice. To their surprise, V40G seeded aggregates even better than wild-type α-synuclein did. Four weeks after injection, mice that had received V40G had far more α-synuclein pathology in the rhinal cortex than did mice treated with wild-type protein. Why might this be? The researchers analyzed gene expression in injected brains to glean clues. They found heightened inflammatory and innate immune responses in V40G-treated animals relative to those treated with wild-type α-synuclein. Supporting this, levels of the inflammatory cytokine IL-1β shot up in numerous brain regions after V40G administration, and this spike preceded the spread of α-synuclein aggregates to these regions. Treating mice with the anti-inflammatory drug lenalidomide along with V40G prevented this spike in IL-1β.

Based on these findings, researchers proposed a new model of α-synuclein propagation. Perhaps α-synuclein oligomers kick off microglial activation and cytokine release, and this inflammatory microenvironment then aggravates nearby neurons, causing α-synuclein to clump up in their cell bodies. By this logic, rather than α-synuclein aggregates passing directly from neuron to neuron, microglia would be essentially the conveyor belt for α-synuclein pathology.

Unity Biotechnology’s Locally Administered Senolytic Trials

Unity Biotechnology has raised an enormous amount of funding from investors and the public markets in order to advance a pipeline of small molecule senolytic drugs. They are presently somewhat ahead of the numerous other senolytic startup biotechnology companies in terms of the road to the clinic. Senolytic compounds are those that can selectively destroy senescent cells in old tissues, thereby removing the contribution of these cells to the aging process. This is literally rejuvenation, albeit quite narrowly focused on just one of the many causes of aging.

It is disappointing that Unity Biotechnology principals are either choosing a strategy of local administration of their drugs, or are forced into it because they consider the drugs too toxic for systemic administration. Senescent cells cause chronic inflammation via secreted signal molecules, the senescence-associated secretory phenotype (SASP). While researchers have demonstrated benefits to local clearance of senescent cells in in joints, gaining regulatory approval for only local administration blocks the vast opportunity for off-label use as a general rejuvenation therapy. That only emerges for compounds that can be systemically administered to destroy senescent cells throughout the body.

To hear Nathanial David tell it, the osteoarthritis drug his Unity Biotechnology began testing in human subjects last fall is about far more than just helping aging weekend warriors regrow cartilage in their damaged knees. It’s the first step toward making us all feel young again. David, was explaining the science behind UBX0101, the drug Unity has in late phase 1 clinical trials to treat the intractable arthritic condition, which affects 14 million Americans. The company is expected to release early results within the next several weeks.

The potential payoff from the company’s arthritis drug ensures investors are watching carefully. After collecting 222 million in venture capital from Jeff Bezos, Peter Thiel, Fidelity, and others on the strength of its preclinical studies, Unity went public last May, raising 85 million in an initial public offering that valued the biotech at 700 million. In 2017 researchers funded by Unity demonstrating that removing senescent cells from the injured knees of mice using UBX0101 not only reduced pain, but also prompted the joint to regrow cartilage. The scientists later repeated the finding using human knee tissue removed from patients who’d undergone total joint replacements.

Last fall doctors began injecting UBX0101 into the knees of older human patients suffering from moderate to severe osteoarthritis. Unity’s selection of osteoarthritis of the knee as its first target allows the team to administer the drug locally in the joint and closely monitor how it affects the aged cells around it. Unity announced earlier this year that it’s also seeking FDA approval to begin human testing for a second locally administered drug, UBX1967, that would target age-related eye diseases.

MicroRNA-199 Produces Significant Heart Regeneration in Pigs

This is one of the more promising animal studies of heart regeneration that I recall seeing in recent years, particularly given that it is accomplished in pigs, which are a good match in size for human tissues. The heart is one of the least regenerative organs in the mammalian body, and damage, such as that resulting from a heart attack, results in scar tissue and loss of function rather than healing. Here, researchers used a microRNA in order to provoke native cells into regenerative activities that would not normally take place. One of the major goals of the regenerative medicine community over the past two decades has to been to find ways to either deliver cells capable of regrowth or to deliver instructions to native cells that will cause them to heal the damaged tissues.

Myocardial infarction, more commonly known as a heart attack, caused by the sudden blocking of one of the cardiac coronary arteries, is the main cause of heart failure. At present, when a patient survives a heart attack, they are left with permanent structural damage to their heart through the formation of a scar, which can lead to heart failure in the future. This is in contrast to zebrafish and salamanders, which can regenerate the heart throughout life. In a new study, the team of investigators delivered a small piece of genetic material, called microRNA-199, to the heart of pigs, after a myocardial infarction which resulted in the almost complete recovery of cardiac function at one month later.

This is the first demonstration that cardiac regeneration can be achieved by administering an effective genetic drug that stimulates cardiac regeneration in a large animal, with heart anatomy and physiology like that of humans. “It is a very exciting moment for the field. After so many unsuccessful attempts at regenerating the heart using stem cells, which all have failed so far, for the first time we see real cardiac repair in a large animal. It will take some time before we can proceed to clinical trials. We still need to learn how to administer the RNA as a synthetic molecule in large animals and then in patients, but we already know this works well in mice.”

Evidence for the Mutation Accumulation Hypothesis of the Origin of Aging

Researchers here examine the growing vaults of genomic data for evidence to support the theory that aging evolves because evolutionary selection is inefficient when it comes to genes variants that have harmful effects in later life. Selection acts most readily on variants that aid reproductive success in early life. Thus variants that are damaging in late life accumulate, reinforcing an age-related decline of health and robustness. This is closely related to the concept of antagonistic pleiotropy, which refers to genes and biological systems that are beneficial in youth but become harmful in later life. These will tend to be selected for, with all of the attendant unpleasant consequences for individual members of the species.

Medawar’s mutation accumulation hypothesis explains aging by the declining force of natural selection with age: Slightly deleterious germline mutations expressed in old age can drift to fixation and thereby lead to aging-related phenotypes. Although widely cited, empirical evidence for this hypothesis has remained limited. Here, we test one of its predictions that genes relatively highly expressed in old adults should be under weaker purifying selection than genes relatively highly expressed in young adults.

Combining 66 transcriptome datasets (including 16 tissues from five mammalian species) with sequence conservation estimates across mammals, here we report that the overall conservation level of expressed genes is lower at old age compared to young adulthood. This age-related decrease in transcriptome conservation (ADICT) is systematically observed in diverse mammalian tissues, including the brain, liver, lung, and artery, but not in others, most notably in the muscle and heart. Where observed, ADICT is driven partly by poorly conserved genes being up-regulated during aging. In general, the more often a gene is found up-regulated with age among tissues and species, the lower its evolutionary conservation. Poorly conserved and up-regulated genes have overlapping functional properties that include responses to age-associated tissue damage, such as apoptosis and inflammation. Meanwhile, these genes do not appear to be under positive selection.

Hence, genes contributing to old age phenotypes are found to harbor an excess of slightly deleterious alleles, at least in certain tissues. This supports the notion that genetic drift shapes aging in multicellular organisms, consistent with Medawar’s mutation accumulation hypothesis.

An Analysis of Six Decades of Change in the Variability of Human Life Span

Inequality is something of a fixation these days; all too many people think that addressing inequality via forced reallocation of the wealth that exists is more important than generating more wealth for all through technological progress. That way lies only ruins. The growth of capabilities and wealth provided by technological progress must be the most important goal, above all others, particularly if we are to develop and benefit from rejuvenation biotechnologies.

Still, all too many people focus on inequality to the exclusion of progress, and inequality, not progress, is the hot button topic of the moment. Thus this paper on variability of human life span over time is presented as a discussion on inequality. Nonetheless, after skipping the rhetoric, the data is quite interesting. The years since 1950 have seen staggering advances in the state of medical technology, unevenly distributed between regions of the world, but the long term direction near everywhere is onward and upward. Despite this uneven distribution of wealth and technology, it seems that most of the variation in human life span is not found between wealthy and less wealthy regions, which may be a surprise to some observers.

Living a long and healthy life is among the most highly valued and universal human goals, so the unparalleled longevity gains recorded all over the world during the last few decades are cause for celebration. While a huge body of scholarship has shed considerable light on the ‘efficiency part’ of the process (i.e., the global, regional and national trajectories in life expectancy over time are very well documented), much less is known about the ‘equality part’. Since mortality can arguably be considered the ultimate measure of health, lifespan inequalities should be seen as the most fundamental manifestations of health disparities.

Studies on lifespan disparities usually focus their attention on differences occurring either between or within countries. The former approach typically compares the average health performance among a cross-section of countries (most often by comparing the corresponding life expectancies) and aims at understanding why population health is better in some countries than in others. In contrast, the latter approach explores the lifespan differences that might exist among the individuals within a given country. Surprisingly, the study of global lifespan inequality – that is, the study of variations in individuals’ lifespan both within and between all world countries – is largely underdeveloped.

Our findings indicate that (i) there has been a sustained decline in overall lifespan inequality, (ii) adult lifespan variability has also declined, but some plateaus and trend reversals have been identified, and (iii) lifespan inequality among the elderly has increased virtually everywhere. All these changes have occurred against a backdrop of generalized mortality reductions. While such an increase in elderly lifespan inequality should be expected in the context of increasing longevity, it is nonetheless important to document which countries or regions are spearheading the process and which ones are lagging behind.

The increase in lifespan variability among the elderly was previously investigated in a selected group of highly industrialized countries. According to the authors of that study, the systematic increases in longevity alter the health profile of survivors in fundamental ways: advances in medicine, socioeconomic conditions, and public health planning have facilitated frailer individuals reaching more advanced ages, thus increasing the heterogeneity in health profiles among the elderly. As shown in this paper, it turns out that such mechanisms might have been operating not only in high-income settings but also across all world countries and regions, irrespective of their stage in the demographic or epidemiological transitions.

Decomposing global lifespan inequality levels into within- and between-country components, we observe that most of the world variability in ages at death can be explained by differences occurring within countries. Depending on the inequality measure and the period we choose, the within-country component explains approximately 85% and 95% of the total variation. This suggests that traditional narratives in global health disparities focusing on international variations in life expectancy neglect the major source of lifespan inequality: the source that takes place within countries. This is precisely the component that has experienced the most dramatic changes during the last six decades. Indeed, our counterfactual analyses suggest that the observed changes in global lifespan inequality can be largely attributable to the changes in within-country lifespan distributions, while the contributions of increasing longevity and differential population growth have played a relatively minor role.

Since most lifespan variability takes place within countries, focusing on the trends of central longevity indicators alone disregards the major source of variability, thus potentially arriving at overly simplistic conclusions. During recent decades, much progress has been made in increasing longevity while reducing age-at-death variability across the full lifespan and, to a lesser extent, across adult ages. However, we now appear to face a new challenge: the emergence of diverging trends in lifespan inequality among the elderly around the globe. While lifespan inequality is increasing among the elderly across virtually all world countries, longevity and heterogeneity in mortality among the old has increased faster in the richer regions of the globe.

Mitochondrial Dysfunction as a Contributing Cause of Osteoporosis

Bone is constantly remodeled throughout life through the actions of osteoblasts, cells that build bone, and osteoclasts, cells that break down bone. The proximate cause of osteoporosis, the age-related loss of bone mass and strength, is a growing imbalance between these cell types that favors osteoclasts. Why does this happen? Chronic inflammation generated by the presence of senescent cells appears to be one cause, as cells react to inflammation in ways that favor osteoclast ativity over osteoblast activity. Researchers here provide evidence for the age-related decline in mitochondrial function to be important as well, another mechanism that ensures more osteoclasts than osteoblasts are introduced into bone tissue.

Some risk factors for osteoporosis such as being older and female or having a family history of the condition cannot be avoided. But others can, like smoking cigarettes, consuming alcohol, taking certain medications, or being exposed to environmental pollutants. But until now researchers haven’t gained a firm picture of how these exposures link up with bone loss. A new study reveals a mechanism by which these factors and osteoporosis may be linked. Damage to mitochondria – key cellular organelles and energy generators – leads to a surge in the creation of cells called osteoclasts, which are responsible for breaking down bone.

The scientists took a close look at how problems with mitochondria affected a type of immune cell known as macrophages. Macrophages are a front line for the immune system, engulfing and digesting foreign invaders to the body. But macrophages can also diversify, transforming into osteoclasts when the circumstances are right. To understand how mitochondrial damage could be linked to osteoporosis through the work of macrophages, the researchers induced damage to a key enzyme responsible for energy production in mitochondria, cytochrome oxidase C, in lab-grown mouse macrophages. Doing so led the macrophages to release a variety of signaling molecules associated with an inflammatory reaction and also seemed to encourage them to go down the path toward becoming osteoclasts.

Looking closely at what was going on, they observed an anomaly with a key molecule, RANK-L, that helps regulate the bone-rebuilding process and is released by bone-building cells as a means of inducing bone break-down. When mitochondria were damaged, they underwent stress signaling and transformed into osteoclasts at a much faster rate, even when RANK-L levels were low. These osteoclasts led to greater rates of bone resorption, or break down. The researchers confirmed their findings in a mouse model, showing that animals with a mutation that leads to dysfunctional mitochondria had increased production of osteoclasts. Because some of the same environmental risk factors that seem to promote osteoporosis, like smoking and some pharmaceuticals, can also impact mitochondrial function, the team posits that this stress signaling might be the pathway by which they are acting to affect bone health.

Rejuvenate Bio to Launch a Gene Therapy Trial for Heart Failure in Dogs

One of the many possible paths towards developing a new medical technology is to first focus on veterinary use. It is considerably less costly in time and resources to develop a therapy for dogs, say, than it is to develop a therapy for humans. Later, given robust success in veterinary medicine, the therapy can be brought into the sphere of human medicine. This is the approach taken by Rejuvenate Bio for their class of regenerative gene therapies. As noted here, the company is moving forward to trials in companion animals, starting later this year.

Back in 2015, the Church lab at Harvard began testing a variety of therapies focused on age reversal using CRISPR, a gene editing system that was much easier and faster to use than older techniques. Since then, Professor Church and his lab have conducted a myriad of experiments and gathered lots of data with which to plan future strategies for tackling aging. Last year, we learned that Rejuvenate Bio had already conducted some initial studies with beagles and were planning to reverse aging using CRISPR gene therapy. The goal was to move these studies forward to a larger scale as a step towards bringing similar therapies to humans to prevent age-related diseases.

Choosing to develop therapies for dogs helps pave the way for therapies that address the aging processes in humans and could support their approval, which would otherwise be much more challenging. If Rejuvenate Bio can produce robust data in dogs showing that some processes of aging have been reversed, it lends considerable justification for human trials. The company is also taking a different tack; instead of focusing on increasing lifespan, it is instead targeting an age-related disease. Rejuvenate Bio will be launching a gene therapy trial in dogs during the fall this year to combat mitral valve disease (MVD), a condition commonly encountered in the Cavalier King Charles Spaniel breed and directly caused by the aging processes. The study will initially focus on this particular breed and expand to include other dogs with MVD as time passes.

This gene therapy is focused on adding a new piece of DNA into the cells of the dogs in order to halt the buildup of fibrotic scar tissue in the heart, which is linked to the progression of MVD and other forms of heart failure. Fibrotic tissue is the result of imperfect repair, which occurs when a more complete repair is not possible due to a lack of replacement cells or high levels of inflammation. The therapy may also be useful for other heart conditions, such as dilated cardiomyopathy (DCM). If the initial results are successful, we could see more dog breeds included as well as other conditions, including DCM, added to the program.

Aging, Metabolic Rate, and the Differences Between Birds and Mammals

There is a strong association in mammalian species between metabolic rate, size, and life span. When pulling in bird species to compare, however, it is observed that they tend to have higher metabolic rates and longer life spans at a given size. So the question here is what exactly is going on in bird metabolism that allows for this more heated operation of cellular metabolism, necessary to meet the demands of flight, without the consequences to life span observed in mammalian species. The open access paper here is illustrative of research in this part of the comparative biology of aging field. Is there anything in this ongoing work on metabolism and aging that might one day lead to methods of extending mammalian life? Perhaps, perhaps not. Altering the operation of metabolism is a poor second best to repairing the damage that causes aging, but one never knows what might emerge from fundamental research at the end of the day.

Mitonuclear communication is at the heart of metabolic regulation, especially in fundamental processes such as cellular respiration. All endothermic organisms have evolved high metabolic rates for increased heat production. However, birds and mammals evolved endothermy independently of each other, and demonstrate some stark differences. Birds live significantly longer lives compared with mammals of similar body size, despite having higher metabolic rates, body temperatures, and blood glucose concentration.

The underlying physiological mechanisms that explain differences between mammals and birds are varied, and include differences at tissue- and cell-levels. For both of these groups, mass-specific basal metabolic rate (BMR) decreases with body size and body size accounts for much of the variation in BMR, however, much variation among species still remains to be explained. Because BMR is defined fundamentally as the sum of tissue metabolic rates, it follows that variation in BMR may relate to the relative size of central organs.

Alternatively, cellular machinery of the tissues of birds and mammals may differ. Metabolic intensity of tissues is thought to vary because of differences in numbers of mitochondria within cells, concentrations of metabolic enzymes, activity or quantity of the membrane sodium-potassium ATPase pump, and the number of double bonds in fatty acids of cell membranes. Because of differences in whole-organism metabolic rate, we may also expect differences within the rates of cellular processes, including oxidative stress.

Oxidative stress is a balance, inherent to all aerobic organisms, between the potential damage that could be accrued by reactive oxygen species (ROS) and the resources cells have to thwart that damage through the antioxidant system. This process has gained momentum in the ecological physiology literature because it has been implicated in determining rates of aging. Here, we sought to quantify parts of the oxidative stress system in a diverse group of birds and mammals. Our question was two-fold: does oxidative stress (a product of aerobic respiration and thus BMR) scale with body mass in these two groups? And are there differences in oxidative stress between birds and mammals?

Our first finding is that cellular metabolism and every parameter that we measured to quantify oxidative stress in birds and mammals does not scale with body mass. This implies that differences at the cellular level might make small contributions to scaling at the organ level, pointing to the fact that scaling of metabolism may reside in higher levels of organization. An obvious explanation may be that organ sizes between similarly-sized birds and mammals may be disproportionally larger in birds compared with mammals, leading to higher BMR.

Secondly, birds showed significantly lower basal cellular oxygen consumption, lipid oxidative damage, and lower activities of catalase. These results together imply several possible physiological mechanisms, none of which are mutually exclusive: (i) birds may have cells with significantly fewer mitochondria or with mitochondria that are more uncoupled; (ii) birds may be less burdened by ROS production compared with mammals; or (iii) birds may have membranes with lower membrane polyunsaturation compared with mammals.

The DNA Damage Response Falters in Old Stem Cells

Efficient DNA repair is necessary to prevent cells from becoming dysfunctional or senescent in response to stochastic nuclear DNA damage. This is particularly important in stem cell populations, as there is no outside source to replace their losses, or repair persistent dysfunction. Researchers here note that the DNA damage response fails to trigger sufficiently in old intestinal stem cell populations, and this may be an underlying contributing cause of higher levels of cellular senescence in these cells.

Aging is related to disruption of tissue homeostasis, which increases the risks of developing inflammatory bowel diseases (IBDs), and colon cancer. However, the molecular mechanisms underlying this process are largely unknown. Various age-related dysfunctions of adult tissue-resident stem/progenitor cells (TSCs, also known as somatic stem cells) are associated with perturbation of tissue homeostasis. Restoration of stem cell functions has attracted much attention as a promising therapeutic strategy for geriatric diseases.

The intestinal epithelium is one of the most rapidly renewing tissues in the body. Lgr5-expressing intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. Therefore, dysfunction of ISCs may be important for the disruption of intestinal homeostasis and subsequent induction of functional disorders. However, the influence of aging on the functions of ISCs and induction of diseases is largely unknown.

Recent studies demonstrated that accumulation of senescent cells promotes organismal aging. Cells become senescent in response to various aging stresses, such as oxidative stress, telomere shortening, inflammation, irradiation, exposure to chemicals, and the mitotic stress, all of which induce DNA damage. Numerous types of DNA damage occur naturally and are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. The mutation rate is highest in the small and large intestines. However, the influence of aging on the DDR in ISCs has not been studied.

Here, we compared induction of the DDR, inflammation, and mitochondrial biogenesis upon irradiation between young and old mouse ISCs in vivo. Induction of the DDR and expression of associated proteins were decreased in old ISCs. The DDR was sustained in old differentiated cells, suggesting that only the responsiveness to DNA damage was perturbed and DDR capacity was potentially sustained in old ISCs. Our results suggest that the competence of the DDR in ISCs declines with age in vivo.

Mitochondrial Function and the Association Between Health and Intelligence

Intelligent people tend to have a longer life expectancy. Is this because they also tend to have more education, be wealthier, and make better lifestyle choices? This web of correlations is hard to untangle. Might there also be underlying physical mechanisms that contribute to this well known association between intelligence and long-term health, however? Are more intelligent people a little more physically robust, on average? There is some evidence for this sort of effect to be present in other species, and some genetic studies suggest that common variants affect both traits, while twin studies also add evidence in favor of physical mechanisms that influence both intelligence and longevity.

Here, researchers argue that variations in mitochondrial function is the mechanism of greatest interest in this matter, as this can affect the energy-hungry tissues of both brain and heart muscle. Mitochondria are the power plants of the cell, packaging chemical energy store molecules to power cellular processes. It is well known that mitochondrial function is important in aging, and declines with age. If an individual has a slightly more efficient mitochondrial population, or mitochondria that are just a little more resilient to the molecular damage of aging, perhaps that will be enough for both improved brain function throughout development and adult life, and a slower decline into age-related disease and mortality.

For over 100 years, scientists have sought to understand what links a person’s general intelligence, health and aging. In a new study, scientists suggest a model where mitochondria, or small energy producing parts of cells, could form the basis of this link. This insight could provide valuable information to researchers studying various genetic and environmental influences and alternative therapies for age-related diseases, such as Alzheimer’s disease. “There are a lot of hypotheses on what this link is, but no model to link them all together. Mitochondria produce cellular energy in the human body, and energy availability is the lowest common denominator needed for the functioning of all biological systems. My model shows mitochondrial function might help explain the link between general intelligence, health, and aging.”

The insight came while working on a way to better understand gender-specific vulnerabilities related to language and spatial abilities with certain prenatal and other stressors, which may also involve mitochondrial functioning. Mitochondria produce ATP, or cellular energy. They also respond to their environment, so habits such as regular exercise and a diet with fruits and vegetables can promote healthy mitochondria. “These systems are being used over and over again, and eventually their heavy use results in gradual decline. Knowing this, we can help explain the parallel changes in cognition and health associated with aging. Also with good mitochondrial function, the aging processes will occur much more slowly. Mitochondria have been relatively overlooked in the past, but are now considered to relate to psychiatric health and neurological diseases. Chronic stress can also damage mitochondria and that can affect the whole body – such as the brain and the heart – simultaneously.”

Nematodes are Probably Not Useful Models of Mitochondrial Aging

Mitochondria, the power plants of the cell, carry their own DNA, encoding a few proteins essential to mitochondrial operation. Mutational damage to these genes can result in broken mitochondria that take over cells and cause the export of oxidizing molecules, contributing to the progression of aging. Not all mitochondrial DNA damage is the same, however: point mutations versus deletion mutations, for example. Researchers have struggled to produce consistent data in mice and nematodes with increased levels of mitochondrial DNA damage of various sorts. Some mice engineered to have greater mutation rates in mitochondrial DNA exhibit accelerated aging, while others do not, with little sign of a coherent explanation as to why beyond the sentiment that short-lived species are not useful models in this case.

The work here in nematodes, using radiation to produce mitochondrial DNA damage, should probably taken as more in the same vein. The researchers find no correlation between damage levels and life span, and this may well be because they are not introducing the right sort of mutational damage that occurs over the course of aging in longer-lived species. It is thought that deletion mutations, or other equally drastic damage, is necessary, for example. But nematodes do not accumulate such damage over the course of their very short lives. They may just be a very poor model for any consideration of the mitochondrial contribution to the aging process.

The mitochondrial free radical theory of aging (mFRTA) proposes that accumulation of oxidative damage to macromolecules in mitochondria is a causative mechanism for aging. Accumulation of mitochondrial DNA (mtDNA) damage may be of particular interest in this context. While there is evidence for age-dependent accumulation of mtDNA damage, there have been only a limited number of investigations into mtDNA damage as a determinant of longevity. This lack of quantitative data regarding mtDNA damage is predominantly due to a lack of reliable assays to measure mtDNA damage.

Here, we report adaptation of a quantitative real-time polymerase chain reaction (qRT-PCR) assay for the detection of sequence-specific mtDNA damage in C. elegans and apply this method to investigate the role of mtDNA damage in the aging of nematodes. We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in reactive oxygen species detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found that there is no simple relationship between mtDNA damage and lifespan.

In order to more directly test the relevance of mtDNA damage in the context of lifespan determination, we introduce damage to mtDNA directly by exposing young C. elegans to UV- or γ-radiation. Sufficiently high levels of UV-radiation cause extensive mtDNA damage and this indeed shortened C. elegans lifespan. However, we found that lower levels of this stressor still significantly increase mtDNA damage but without causing significant detriments and that some levels even resulted in lifespan extension and healthspan improvements.

This is consistent with the concept of hormesis; that exposure to mild stress, through evoking adaptive responses and strengthening stress defense mechanisms can lead to lifespan extension. However, it is worth noting that in our experiments, even under conditions where UV damage results in hormetic benefits, damage remained detectably elevated, even on the day following exposure. The lack of evidence for a tight relationship between mtDNA damage burden and lifespan in C. elegans is consistent with our recent finding that, most likely due to the short lifespan of nematodes, mtDNA deletion do not accumulate with age in C. elegans.

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