Fight Aging!

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Contents

• The Influence of Lifestyle Choices on Survival to Age 85
• Another Clinical Trial Assessing the Effects of Urolithin A on Muscle Strength and Mitochondrial Function
• Reviewing What is Known of Alternative Lengthening of Telomeres
• Evaluating Intermittent Hypoxia as a Basis for Therapy
• Reviewing Mechanisms of Aging that Drive the Aging of the Brain
• Targeting the Artery-Brain Circuit in Atherosclerosis
• Commentary on Reprogramming from Yuri Deigin of YouthBio Therapeutics
• Fisetin Reduces the Burden of Senescent Cells in the Vasculature of Mice
• Exercise Upregulates BDNF Expression to Promote Dopamine Release and Brain Function
• The Implications of Cross-Species Epigenetic Clocks
• Constraints Due to the Interconnected Nature of Cellular Biochemistry in the Evolution of Aging
• An Age-Related Reduction in Tom70 is Relevant to Mitochondrial Aging
• Cyclic FOXM1 Upregulation Extends Life in Aged Mice
• A Discussion of Progress Towards Reprogramming Therapies with a Turn.bio Co-Founder
• NF-κB in Age-Related Inflammation and Immunosenescence

The Influence of Lifestyle Choices on Survival to Age 85
https://www.fightaging.org/archives/2022/05/the-influence-of-lifestyle-choices-on-survival-to-age-85/

If decent odds of living into late old age are the desired goal, in the present medical environment in which the easily available, widely used technologies still have comparatively little impact on aging and age-related disease, then good lifestyle choices are paramount. Don't smoke. Stay thin. Eat a good diet. That lifestyle choices have a sizable impact on aging in comparison to available medical technologies is a sign that the research and development communities are not yet very far along in the treatment of aging. We might hope that this will change in the years ahead, starting with the widespread use of first generation senolytic therapies to remove senescent cells and the harms that they cause.

How large an effect on life expectancy results from good versus bad lifestyle choices? Epidemiological studies such as that noted in today's open access paper can be used to answer this question. People making poor lifestyle choices had a 28% chance of reaching age 85, while people making better lifestyle choices had a 67% chance of reaching age 85. While no-one gets to be 85 with a youthful physique, at least not until rejuvenation therapies are a lot further along, there is something to be said for being alive versus the alternative, particularly as progress in medical technology will continue along the way, offering better options as time goes on.

Healthy Choices in Midlife Predict Survival to Age 85 in Women: The Tromsø Study 1979-2019

The aim of this study is to examine the association between single risk factors and multiple risk factors in midlife and older ages (up to 64 years) and survival to the age of 85 years in women. The study sample comprised 857 women who attended the second survey of the population-based Tromsø Study (Tromsø2, 1979-1980) at the ages of 45-49 years and were followed for all-cause mortality until 85 years of age. Daily smoking, physical inactivity, being unmarried, obesity, high blood pressure, and high cholesterol in midlife were used as explanatory variables in survival analyses.

In total, 56% of the women reached the age of 85. Daily smoking, physical inactivity, being unmarried, and obesity were significant single risk factors for death before the age of 85. None of the women had all six risk factors, but survival to age 85 did decrease gradually with increasing number of risk factors: from 67% survival for those with no risk factors to 28% survival for those with four or five risk factors. A subset of the study sample also attended the third and fourth surveys of the Tromsø Study (Tromsø3, 1986-1987 and Tromsø4, 1994-1995, respectively).

Women who quit smoking and those who became physically active between Tromsø3 and Tromsø4 had higher survival when compared to those who continued to smoke and remained physically inactive, respectively. This study demonstrates the importance of having no or few risk factors in midlife with respect to longevity. We observed a substantial increase in the risk of death before the age of 85 among women who were daily smokers, physically inactive, unmarried, or obese in midlife. This risk may be mitigated by lifestyle changes, such as quitting smoking and becoming physically active later in life.

Another Clinical Trial Assessing the Effects of Urolithin A on Muscle Strength and Mitochondrial Function
https://www.fightaging.org/archives/2022/05/another-clinical-trial-assessing-the-effects-of-urolithin-a-on-muscle-strength-and-mitochondrial-function/

Urolithin A is one of a number of supplements under assessment for their ability to improve mitochondrial function in older adults. Mitochondria are the power plants of the cell, producing chemical energy store molecules vital to all cellular processes. Improved mitochondrial function should result in improved tissue function throughout the body, such as in skeletal muscle, a tissue with high energy requirements. You might recall the results published from a small human study earlier this year. Some measures of strength and endurance were improved, but as is the case for other, similar approaches to reducing age-related mitochondrial dysfunction, the gains are not as large as those that can be obtained via structured exercise programs. It is questionable as to whether significant time and funding should be devoted to these approaches.

Mitochondrial function declines with age, and evidence to date suggests that loss of efficacy in mitophagy is an important part of this aspect of degenerative aging. Mitophagy is a complex process of many stages in which damaged and worn mitochondria are identified, transported to a lysosome, and broken down. Defects in any part of this process, such as a reduced expression of critical proteins due to age-related changes in epigenetic regulation, will reduce overall efficiency of mitophagy. When mitophagy falters, dysfunctional mitochondria accumulate to the detriment of the cell. Urolithin A is thought to produce its benefits to mitochondrial function by restoring greater efficiency in mitophagy, though exactly how this is achieved is up for debate.

Clinical study shows postbiotic urolithin a improves muscle strength and exercise performance in middle aged adults

A new study shows that daily intake of Urolithin A significantly improved muscle strength by 12% after four months. This works by supporting the cells' ability to renew their power plants, the mitochondria, during the aging process. Muscles have a high demand for energy and there are a very large number of mitochondria in muscle cells.

Two measures of skeletal muscle strength were improved in the supplemented groups compared to the placebo group. Muscle strength in the hamstring skeletal muscle was significantly increased in both 500mg (+12%) and 1,000mg groups (+9.8%). Muscle strength during knee flexion was also significantly improved at both 500mg (+10.6%) and 1,000mg doses (+10.5%). The blood tests and biopsies showed a significant improvement in biomarkers of healthy mitochondrial function and reduced inflammation.

Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults

Targeting mitophagy to activate the recycling of faulty mitochondria during aging is a strategy to mitigate muscle decline. We present results from a randomized, placebo-controlled trial in middle-aged adults where we administer a postbiotic compound Urolithin A, a known mitophagy activator, at two doses for 4 months (NCT03464500). The data show significant improvements in muscle strength (∼12%) with intake of Urolithin A. We observe clinically meaningful improvements with Urolithin A on aerobic endurance (peak oxygen oxygen consumption [VO2]) and physical performance (6 min walk test) but do not notice a significant improvement on peak power output (primary endpoint).

Levels of plasma acylcarnitines and C-reactive proteins are significantly lower with Urolithin A, indicating higher mitochondrial efficiency and reduced inflammation. We also examine expression of proteins linked to mitophagy and mitochondrial metabolism in skeletal muscle and find a significant increase with Urolithin A administration.

Reviewing What is Known of Alternative Lengthening of Telomeres
https://www.fightaging.org/archives/2022/05/reviewing-what-is-known-of-alternative-lengthening-of-telomeres/

All cancerous cells must lengthen their telomeres in order to continue unfettered, harmful replication. Telomeres are repeated DNA sequences at the ends of chromosomes. A little telomere length is lost with each cell division, and cells with short telomeres following repeated replication become senescent or self-destruct. This is how the Hayflick limit on somatic cell replication is enforced. Unlike somatic cells, stem cells are privileged, and use telomerase to lengthen telomeres in order to produce daughter somatic cells via replication throughout life. Cancer cells, on the other hand, use either telomerase (~90% of cancers) or a partially explored set of mechanisms called alternative lengthening of telomeres (ALT, ~10% of cancers).

In this context, I'll mention what I think to be a good idea for a new biotech venture, suitable for someone who likes to take on a little more risk at the outset. Set forth to conduct a program of screening for small molecules that interfere in ALT. The aim is to discover compounds that can be used to treat the 10% of cancers that employ ALT, shutting down their ability to replicate. This is a somewhat open part of the field, as little funding goes towards such pure, focused discovery efforts in comparison to the funding for groups that already have an identified small molecule. Yet it is a reasonable wager that a large enough screening effort will turn up something useful along the way.

ALT is an attractive target for drug development. It only operates in cancerous cells, not normal cells, so there are fewer concerns regarding off-target effects. Interfering in ALT is a necessary part of a future universal cancer therapy that comprehensively prevents telomere lengthening. This is the best and most fundamental way to eliminate cancer, an approach that cancers can neither evade nor evolve resistance to. Even 10% of cancers is a vast market for one drug. The SENS Research Foundation tried a modestly sized screening program a few years ago, and didn't find good targets. Since then the research community has uncovered new information that might lead to a more guided screening process, such as the roles of FANCM and TRIM28. It is worth a try!

Alternative Lengthening of Telomeres and Mediated Telomere Synthesis

Telomeres are located at the end of eukaryotic chromosomes, and in humans, they are composed of TTAGGG tandem repeat DNA sequences and telomere-binding proteins. They are special structures that do not carry genetic information, and they comprise a proximal double-stranded region and the distal single-stranded region. Telomeres prevent the loss of genetic information during DNA replication and protect chromosomes from end fusion. Except in embryonic germ cells, stem cells, and cancer cells, telomere length gradually shortens with cell division. Short or dysfunctional telomeres are recognized as double-strand breaks (DSBs), triggering replicative senescence of cells.

Telomere maintenance is essential for genomic stability and survival of proliferating cells. To escape from the "Hayflick limit", the majority of tumor cells reactivate telomerase, which maintains telomere length. Telomerase maintains telomere length by adding telomere DNA repeats to the end of telomeres. This enzyme consists of a protein component with reverse transcriptase activity and an RNA component that is the template for telomeric DNA synthesis. However, approximately 10 to 15% of human tumors preferentially maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, which is a potential therapeutic target for telomerase-negative tumors.

The ALT phenotype has been observed in a broad range of human cancers, and some ALT-related cancers are aggressive. However, the development of anti-cancer therapeutics targeting the ALT pathway has been greatly limited by a failure to understand the molecular mechanisms underlying ALT pathway action and initiation. Here, we review recent discoveries regarding the ALT pathway mechanism and discuss possible cancer therapy targets in the ALT pathway.

Evaluating Intermittent Hypoxia as a Basis for Therapy
https://www.fightaging.org/archives/2022/05/evaluating-intermittent-hypoxia-as-a-basis-for-therapy/

Many forms of mild, intermittent stress produce an overall net benefit to cell and tissue function: low nutrient intake; heat; cold; excessive oxidative molecules; some toxins; and the topic of today's open access paper, hypoxia. When under stress, cells react with increased maintenance efforts aimed at removing damaged molecules and structures. If the stress is mild or of short duration, then the damage done it outweighed by the ongoing repair carried out. Work on the biochemistry of the beneficial response to calorie restriction suggests that autophagy is the most important of these processes, but there are others. In autophagy, molecules and structures are engulfed in an autophagosome and moved to a lysosome where they are broken down for recycling.

In the research noted here, scientists apply an intermittent hypoxia treatment to older patients for half a year and see a modest improvement in only some measures of metabolic health. Chronic inflammation and fat mass were reduced, though the effect size compares unfavorably with structured exercise programs, as is near always the case in these efforts to upregulate cellular maintenance processes. Additionally, a range of other health parameters remained unchanged, an outcome that definitely compares unfavorably with exercise, which tends to produce benefits across the board.

Intermittent Hypoxia as a Therapeutic Tool to Improve Health Parameters in Older Adults

Oxygen is essential for human life, playing a determining role in aerobic respiration and cellular metabolism. A decrease in oxygen (hypoxia) could be deleterious for cellular adaptation and survival. In addition, sustained hypoxia contributes to functional decline during the aging process. Chronic exposure to severe hypoxia leads to an increased oxidative stress, vasoconstrictor activation, systemic inflammation, hypoxemia, pulmonary hypertension, and myocardial ischemia. Conversely, intermittent exposures to moderate hypoxia could have beneficial health effects in both healthy and diseased individuals.

Intermittent hypoxia (IH), defined as short alternating exposures to hypoxia and normoxia, can change body composition and health status with improved exercise tolerance, metabolism, and systemic arterial pressure. It has also been presented as a promising tool to beneficially impact bone metabolism. IH exposure allows modulating and stabilizing the hypoxia-inducible factor-1 alpha (HIF-1α), which is involved in the expression of factors related to angiogenesis, osteogenesis, lipolysis, and regulation of the inflammatory response.

Previous studies have suggested that IH could positively influence age-related alterations in older adults. The aim of this study was to evaluate the effect of 24 weeks of moderate intermittent hypoxia exposure on parameters related to body composition, inflammation, cardiovascular, and bone health in older adults. We hypothesized that IH intervention will have a positive effect on these health parameters. A total of 38 healthy older adults (aged 65-75 years) were divided into two groups: control group (C), and hypoxia group (H) that was subjected to an intermittent hypoxia exposure (at simulated altitude of 2500 m above sea level) during a 24-week period (3 days/week).

The results obtained have shown that IH exposure leads to beneficial effects on the health of the older adults. However, our initial hypothesis has only been partially fulfilled. After 24 weeks of intervention with IH, there has been a decrease in fat mass and C-reactive protein concentrations, as well as an improvement in blood biomarkers of bone remodeling, but no significant changes have been observed in bone mineral content and bone mineral density, nor in the metabolic and cardiovascular health parameters.

Reviewing Mechanisms of Aging that Drive the Aging of the Brain
https://www.fightaging.org/archives/2022/05/reviewing-mechanisms-of-aging-that-drive-the-aging-of-the-brain/

In today's open access paper, researchers review what is known of the ways in which the hallmarks of aging are involved in the aging of the brain, from initial cognitive decline through to later dementia. Interestingly, chronic inflammation is increasingly implicated in brain aging and the onset of dementia, and many of the hallmarks can be connected to inflammation. This is a direct connection in some cases, such as the presence of senescent cells that generate an outsized amount of pro-inflammatory signaling in comparison to their numbers. Other issues produce inflammation more indirectly, such as the numerous impairments in cell function, including disarray in mitochondrial function, autophagy, and epigenetic patterns, that lead to failure of the blood-brain barrier. That barrier leaks, leading to inflammation as inappropriate molecules and cells make their way into the brain.

Epigenetic aging is an increasingly interesting topic, given the prospect of epigenetic rejuvenation via partial reprogramming. Epigenetic changes that occur with aging are perhaps caused by cycles of DNA damage and repair, causing a depletion of factors needed to maintain youthful epigenetics. Reprogramming causes a reset in epigenetic marks, and resulting benefits in cell function. To what degree do age-related epigenetic changes result in inflammatory behavior in addition to other dysfunctions in cell behavior? That is an interesting question that has yet to be usefully answered. As noted above, the consequence of inflammation many not be a direct outcome of changed cell behavior, and rather lie at the end of a chain of downstream items. The best way to find out is for the research community to continue to apply reprogramming therapies in animal studies and observe the outcomes.

Biological aging processes underlying cognitive decline and neurodegenerative disease

Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. After the age of 65, the incidence of ADRD nearly doubles every 5 years, and by the ninth decade of life, approximately one of every three adults meets criteria for dementia. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms.

Biological pathways underlying normal cognitive aging and ADRD are likely to overlap, existing along a continuum. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. The biology-of-aging field has made substantial gains in identifying the pathophysiological processes that contribute to biological aging and multisystem organ decline.

In a seminal paper, researchers defined nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, altered intercellular communication, and cellular senescence. These aging hallmarks and others have been implicated as pathogenic factors underlying numerous chronic age-related diseases, including ADRD. In animal models, targeting biological aging processes has extended both lifespan and healthspan, suggesting the possibility that these approaches may have beneficial effects for cognitive health as well.

Targeting the Artery-Brain Circuit in Atherosclerosis
https://www.fightaging.org/archives/2022/05/targeting-the-artery-brain-circuit-in-atherosclerosis/

Researchers here discuss evidence for the involvement of the nervous system in the progression of atherosclerosis, the formation of ultimately fatal fatty deposits in blood vessel walls. These atherosclerotic lesions are sites of inflammation, drawing in macrophage cells of the innate immune system that attempt to repair the injury, but become overwhelmed by cholesterol, die, and add their mass to the growing plaque. It also appears that the presence of atherosclerotic plaque activates signals that pass via the nervous system to the brain and then to the spleen. In the spleen, monocyte cells held in reserve are activated, enter the bloodstream, travel to the plaque to become macrophages, and thus make matters worse. Atherosclerosis is a good example of a normally beneficial repair system in the body, the delivery of macrophages to injuries, becoming pathological in later life, causing harm rather than helping.

New research demonstrates for the first time the existence of a connection between atherosclerotic plaques and the central nervous system, which in turn, through the spleen, it activates the immune system, further stimulating the development of the disease. This hitherto unknown "nervous circuit" could represent a target for innovative therapies.

In correspondence with an atherosclerotic plaque an aggregate of immune cells is also formed in the external wall of the blood vessel. This aggregate, called an artery tertiary lymphoid organ (ATLO) and similar to a lymph node, is rich in nerve fibers. This work has shown that through them a direct connection is established between the plaque and the brain. "We were able to see that these signals coming from the plaque, once they reach the brain, influence the autonomic nervous system through the vagus nerve until it reaches the spleen. Here there is an activation of specific cells of the immune system that enter the circulation and lead to the progression of the plaques themselves."

It is a real nervous circuit, which the authors of the research have defined as "ABC" or "artery-brain circuit". And like all circuits, it can be disconnected or modulated. "We have conducted further experiments by interrupting the nerve connections that reach the spleen. In this way, the impulses on the immune cells present in this organ have failed. The result is that the plaques present in the arteries have not only slowed growth, but have stabilized."

Commentary on Reprogramming from Yuri Deigin of YouthBio Therapeutics
https://www.fightaging.org/archives/2022/05/commentary-on-reprogramming-from-yuri-deigin-of-youthbio-therapeutics/

Cellular reprogramming is a hot topic these days, given the vast amount of funding devoted to research and development, and the number of well capitalized new ventures focused on building therapies based on reprogramming. Reprogramming recaptures the process that takes place in the early embryo in which cells become pluripotent, but also reset their epigenetic patterns to restore mitochondrial function and other cellular processes to a youthful configuration. The primary goal of most reprogramming initiatives is to avoid pluripotency and state change in cells, while still restoring youthful epigenetic control of gene expression and cell function - a work in progress, moving ahead with enthusiasm. That said, there are a range of issues that this approach cannot address well, from nuclear DNA damage to persistent molecular waste, but it seems plausible that useful rejuvenation therapies will result from this line of work.

We are trying to translate partial cellular programming, but we have a tight focus right now on humans. Our approach is to use gene therapy to deliver reprogramming genes once into tissues of interest and then activate them with a small molecule. Ultimately, we feel that partial cellular reprogramming will need a tissue-specific approach. Different organs will probably need different reprogramming factors and definitely different dosing regimens.

Our goal is to create tissue-specific gene induction systems that, for a given tissue, can activate a specific set of genes. That platform doesn't even have to be used for partial cellular programming. It could potentially be used for any other gene therapy that needs several different gene cargoes that need to be activated in a different manner.

Eventually, we also want to move away from Yamanaka factors, because they weren't designed for partial programming. They were designed for full reprogramming, and for our purposes are too dangerous, because full reprogramming causes cells to lose their identity. This is something we obviously do not want, so we're looking for other factors that are better suited to partial reprogramming. Basically, the holy grail for us is to split the rejuvenation from the dedifferentiation. We want to just rejuvenate cells if it's possible.

To me, the beauty of partial cellular reprogramming is actually that it doesn't really matter what aging is. We're taking a very pragmatic approach. We absolutely know that a lot of epigenetic changes are driving aging. Do those changes happen in response to stochastic damage? Or because of a program? For practical purposes it doesn't really matter. We have observations that show that partial cellular reprogramming can delay aging and can reverse some hallmarks of aging on the cellular level. We also see some reversal of those hallmarks on an organ level and potentially on a systemic level. There is definitely a delay of aging in the progeric mouse model where they lived up to 50% longer and exhibited better histology of various tissues.

We are taking a pragmatic approach to translating this research to people. We're actually trying to make something useful rather than just taking a dive deep into the fundamental science, which of course is also important and interesting, but we ultimately want to create a therapy for people as quickly as possible.

Fisetin Reduces the Burden of Senescent Cells in the Vasculature of Mice
https://www.fightaging.org/archives/2022/05/fisetin-reduces-the-burden-of-senescent-cells-in-the-vasculature-of-mice/

Senescent cells accumulate with age and produce tissue dysfunction through their pro-growth, pro-inflammatory signaling. Here researchers report on an example of fisetin supplementation reducing the burden of senescent cells in the vasculature of old mice. It also improves other measures of tissue health. The dose used here is not as high as that in the first mouse study to show fisetin clearing senescent cells, but the dosing schedule is longer.

There remains some question as to whether fisetin at suitably high doses will in fact prove to be usefully senolytic in humans, capable of clearing senescent cells to the same degree as in mice. Currently the dasatinib and quercetin combination is the only senolytic with solid human data to show that it works as well in our species as it does in mice. Questions about fisetin will hopefully be answered by the publication of results from ongoing clinical trials sometime in the next few years. If it does turn out to be as good in humans as it is in mice, that will be of great benefit to health in later life.

Age-related vascular endothelial dysfunction is mediated by excess reactive oxygen species (ROS) - mitochondria being a key source - which can reduce nitric oxide (NO) bioavailability. Cellular senescence, a fundamental mechanism of aging, may exacerbate mitochondrial ROS and be a potential therapeutic target to combat age-related vascular dysfunction. This study ran to determine if treatment with the natural flavonoid fisetin improves endothelial function with aging by suppressing cellular senescence, scavenging excess whole-cell and mitochondrial ROS, and increasing NO bioavailability.

Old (27 mo) male C57BL/6 mice were treated with fisetin (50 mg/kg/day) by oral gavage following a 1 week on - 2 week off - 1 week on dosing paradigm. Endothelial function was assessed by ex vivo carotid artery endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) to increasing doses of acetylcholine and sodium nitroprusside, respectively. Electron paramagnetic resonance (EPR) spectroscopy was used to assess vascular mitochondrial ROS.

EDD was greater in fisetin versus control mice (Peak EDD [%]: 97 ± 1 vs 84 ± 3). Fisetin-treated mice had lower vascular abundance of p16, an established marker of cellular senescence (.12 ± .01 vs .19 ± .02 chemiluminescence units). Fisetin-treated mice had lower mitochondrial ROS (2527 ±440 vs 6603 ± 1956 AU). Further, Fisestin-treated mice had lower abundance of vascular p-p66SHC, a recognized marker of mitochondrial oxidative stress (.029 ± .003 vs .049 ± .008 CU) and greater abundance of Mn superoxide dismutase, a mitochondrial antioxidant enzyme (.41 ± .1 vs .20 ± .02 CU).

In conclusion, fisetin supplementation may be a novel strategy to target excess cellular senescence and thereby reduce mitochondrial ROS to improve NO-mediated endothelial function with aging.

Exercise Upregulates BDNF Expression to Promote Dopamine Release and Brain Function
https://www.fightaging.org/archives/2022/05/exercise-upregulates-bdnf-expression-to-promote-dopamine-release-and-brain-function/

Researchers have in the past shown that exercise results in greater amounts of BDNF, which in turn promotes neurogenesis. Here, this line of research is extended to show that exercise results in an increased release of dopamine, and this benefit depends on BDNF upregulation. Dopamine is important in brain function, but the loss of dopamine that takes place in Parkinson's disease, as dopamine-secreting cells are destroyed, is most likely the primary motivation for this study.

Experts have long understood that regular running raises dopamine activity in the brain and may protect nerve cells from damage. In addition, past research has tied exercise-driven boosts in the dopamine-triggering chemical called brain-derived neurotrophic factor (BDNF) and in dopamine levels to improvements in learning and memory. However, the precise way these three factors interact has until now remained unclear.

A new study showed that mice running on a wheel for 30 days had a 40 percent increase in dopamine release in the dorsal stratium, the part of the brain involved in movement, compared to levels in mice that did not exercise. The runners also showed a nearly 60 percent increase in BDNF levels compared to their non-running counterparts. Notably, the increase in dopamine release remained elevated even after a week of rest. Additionally, when BDNF levels were artificially reduced, running did not lead to additional dopamine release.

For the investigation, researchers provided dozens of male mice with unlimited access to either a freely rotating wheel or a locked wheel that could not move. After one month, the team measured dopamine release and BDNF levels in brain slices. They repeated this same process on a new group of rodents, some of which had been genetically modified to produce half as much BDNF as regular mice. "Our results help us understand why exercise alleviates the symptoms of Parkinson's disease, as well as those of neuropsychiatric disorders such as depression. Now that we know why physical activity helps, we can explore it as a means of augmenting or even replacing the use of dopamine-enhancing drugs in these patients."

The Implications of Cross-Species Epigenetic Clocks
https://www.fightaging.org/archives/2022/05/the-implications-of-cross-species-epigenetic-clocks/

It is reasonable to think that interventions successfully targeting one or more mechanisms of aging will produce benefits across all higher animals. The underlying mechanisms of aging are quite universal. Equally, it is reasonable to think that different species are impacted to different degrees by any given mechanism of aging, and thus interventions may produce small or sizable benefits, depending on the details. Researchers here comment on the ability to produce cross-species epigenetic clocks, in that there are patterns of epigenetic marks on equivalent sites in the genome in two or more species that correlate to chronological age in the same way. Does this then imply that a therapy that both reverses this pattern and extends healthy life span in one species can be expected to do the same in the other? Perhaps, but I don't think that to be a sure bet.

DNA methylation profiles have been used to develop biomarkers of aging known as epigenetic clocks, which predict chronological age with remarkable accuracy and show promise for inferring health status as an indicator of biological age. Epigenetic clocks were first built to monitor human aging, but their underlying principles appear to be evolutionarily conserved, as they have now been successfully developed for many mammalian species.

Here, we describe reliable and highly accurate epigenetic clocks shown to apply to 93 domestic dog breeds. The methylation profiles were generated using the mammalian methylation array, which utilizes DNA sequences that are conserved across all mammalian species. Canine epigenetic clocks were constructed to estimate age and also average time to death.

We also present two highly accurate human-dog dual species epigenetic clocks, which may facilitate the ready translation from canine to human use (or vice versa) of antiaging treatments being developed for longevity and preventive medicine. These clocks, which measure methylation levels in highly conserved stretches of the DNA, promise to increase the likelihood that interventions that reverse epigenetic age in one species will have the same effect in the other.

Constraints Due to the Interconnected Nature of Cellular Biochemistry in the Evolution of Aging
https://www.fightaging.org/archives/2022/05/constraints-due-to-the-interconnected-nature-of-cellular-biochemistry-in-the-evolution-of-aging/

Why is degenerative aging near universal in the animal kingdom? The present consensus explanation is that natural selection acts most strongly on early reproductive life, selecting for mechanisms that are beneficial at the outset of life, heedless of later life harms when those mechanisms run awry over time. Yet why is it the case that so many of the mechanisms beneficial in young animals are also harmful in older animals? Why is this inevitable? Here it is argued that this is an outcome of the highly interconnected nature of cellular biochemistry. Every protein has many functions and influences the function of many other proteins. It is near impossible to change anything in a cell without impacting many related processes in some way; any change will have many distinct consequences, some of which will be detrimental.

Aging rate differs greatly between species, indicating that the process of senescence is largely genetically determined. Senescence evolves in part due to antagonistic pleiotropy (AP), where selection favors gene variants that increase fitness earlier in life but promote pathology later. Identifying the biological mechanisms by which AP causes senescence is key to understanding the endogenous causes of aging and its attendant diseases. Here we argue that the frequent occurrence of AP as a property of genes reflects the presence of constraint in the biological systems that they specify.

The claim that AP is important in the evolution of aging implies that many genes must exhibit AP. But why should so many genes have this property? The likely answer here lies in the existence of a high degree of biological constraint, arising from the highly integrated nature of biological systems. As Stephen Jay Gould put it, when discussing the evolution of anatomy: "any adaptive change in a complex and integrated organism must engender an automatic (and often substantial) set of architectural byproducts".

This means that a new allele that alters one trait in a way that enhances fitness can easily affect other traits adversely. To use a simple example: for fundamental thermodynamic reasons increasing ATP production rate reduces ATP yield and vice versa. Therefore a mutation increasing ATP production rate will exhibit AP and reduce ATP yield; here ATP yield is traded off against production rate. This illustrates how AP can arise not only from properties of the molecular biology of genes or their RNA or protein products, which tend to be the focus of accounts of pleiotropy, but also from properties of the systems that those products impact.

An Age-Related Reduction in Tom70 is Relevant to Mitochondrial Aging
https://www.fightaging.org/archives/2022/05/an-age-related-reduction-in-tom70-is-relevant-to-mitochondrial-aging/

Researchers here implicate an age-related reduction in Tom70 levels in the decline in mitochondrial function that takes place in later life. Mitochondria are the power plants of the cell; when their production of the chemical energy store molecule ATP is diminished, then all cell functions suffer as a result. Mitochondrial dysfunction with age is thought to produce a significant contribution to degenerative aging, and a broad range of research and development efforts are devoted to finding ways to address this problem. Research into Tom70 is at a very early stage, so it remains to be seen as to how useful this discovery will be. It seems likely, at the present time, based on what is known now, that the most important approaches to mitochondrial aging will be (a) epigenetic reprogramming to restore youthful expression of relevant proteins and (b) replacement of a patient's mitochondria via intravenous delivery of large numbers of mitochondria manufactured in cell cultures, to be taken up by cells and put to work.

Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins.

Here, we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription, biogenesis, and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mitochondrial DNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan in budding yeast. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.

Cyclic FOXM1 Upregulation Extends Life in Aged Mice
https://www.fightaging.org/archives/2022/05/cyclic-foxm1-upregulation-extends-life-in-aged-mice/

The Lifespan.io team here notes a recent study in which researchers carefully induced greater expression of FOXM1 in aged mice, showing extension of life as a result. FOXM1 overexpression is known to induce greater stem cell activity, but also to push somatic cells towards a more cancer-like phenotype, meaning more growth, more regeneration, more activity. Cancer and regeneration are two sides of the same coin. Regeneration and tissue maintenance are controlled processes, while a cancer is driven by the same mechanisms when they run wild.

Given these connections, it is not too surprising to find that FOXM1 is downregulated in older individuals, perhaps a part of the general decline in stem cell function, regeneration, and growth that is characteristic of aging. There is a trade-off in later life between tissue maintenance and risk of cancer, due to rising levels of molecular damage, and evolution has selected for a slow decline rather than a longer period of vitality with greater risk of sudden death by cancer. As the successes of stem cell treatments and various other pro-regenerative approaches to therapy make clear, it is nonetheless possible to push the body towards greater tissue maintenance without causing a greatly increased risk of cancer.

Forkhead box (FOX) genes are transcription factors: genes that drive the expression of other genes and are known to play an important role in cell proliferation and longevity. FOXM1 is another forkhead box gene that has gained the attention of aging researchers as an important oxidative stress response regulator and one of the major players in tumorigenesis. Previous studies have shown that FOXM1 is decreased in the cells of older healthy people as well as people whose aging is accelerated by Hutchinson-Gilford progeria syndrome.

In this study, the researchers set out to check if it's possible to delay aging by increasing the expression of FOXM1 in progeroid and naturally aged mice. However, instead of inducing the fully functioning FOXM1, a modified gene that did not contain an N-terminal part was chosen. The C-terminal side of FOXM1 plays an important role in transcriptional activity, and the N-terminal side plays a role in the regulation of intracellular processes, such as controlling the segregation of genetic material during cell division. The N-terminal side was also shown to have an autoinhibitory function repressing the activity of the protein at specific cell cycle stages.

Although promising, the results from experiments in progeroid mice might not translate into naturally aging animals. Therefore, the researchers applied truncated FOXM1, using a 3-day-on and 4-day-off scheme, for 80 weeks to 8-week-old naturally aging mice. Remarkably, the treatment extended the lifespan of aged mice by almost 30% compared to controls. Tissue examination revealed that truncated FOXM1 induction rejuvenated multiple organs: aorta, skin, fat, and muscle. The researchers observed reduced muscle atrophy and a higher number of muscle stem cells, along with increased muscle strength. In addition, decreased aortic fibrosis and wall thickening, as well as increased subcutaneous fat, were demonstrated. Confirming previous results, naturally aging mice had downregulated senescence biomarkers in skin, kidney, fat, and muscle following truncated FOXM1 induction.

A Discussion of Progress Towards Reprogramming Therapies with a Turn.bio Co-Founder
https://www.fightaging.org/archives/2022/05/a-discussion-of-progress-towards-reprogramming-therapies-with-a-turn-bio-co-founder/

The Lifespan.io team here talks with one of the co-founders of Turn.bio, one of the first biotech ventures focused on partial reprogramming as a basis for rejuvenation therapies. Their initial technology involves the delivery of lipid nanoparticles that encapsulate mRNA for temporary expression of the Yamanaka factors. Full reprogramming dedifferentiates and rejuvenates cells, turning somatic cells into induced pluripotent stem cells with youthful epigenetic patterns. Epigenetic rejuvenation is desirable, but producing pluripotent cells in the body is not. Partial reprogramming attempts to apply reprogramming factors for long enough to reset epigenetic patterns to a youthful level, but not for so long as to cause cells to change their state. Looking at the field as a whole, the major thrust of present research and development efforts might be viewed as the search for a reliable way to separate dedifferentiation from epigenetic rejuvenation.

We have seen very significant progress during the last two, three years. Back in 2019, many people still thought that this idea of transient cellular reprogramming, or partial reprogramming, was more science fiction than science. Today, mainstream science, researchers, companies around the world are trying to find the best way to rejuvenate cells. Many labs have started working on these ideas since we published our work. I strongly believe that our proprietary approach, which we call ERA (Epigenetic Reprogramming of Aging), holds the greatest promise in regenerative medicine, because it's a finely tuned and controlled way to reset the epigenetic landscape of cells to a more youthful, functional phenotype without impacting their identity, which is obviously a risk factor that's associated with reprogramming.

We will be moving to human trials very soon, hopefully. We're progressing very rapidly on a couple of indications in dermatology and immunotherapy. Soon, we're going to move into at least Phase I clinical trials. I always like to emphasize the fact that Turn as a company is not just about ERA. This is the foundational technology of Turn, but at the same time, since it relies on the delivery of mRNAs that are used to perform that resetting of the epigenetic landscape, we are also working heavily on the cargo (that is, the mRNAs), and on the delivery system. These three are the three pillars of Turn that are going to enable rapid clinical implementation of this technology for a variety of indications. There has been great progress in terms of research on all three of those, but most importantly, there has been major progress recently in partnering up with big players in the pharma field that are mission oriented.

NF-κB in Age-Related Inflammation and Immunosenescence
https://www.fightaging.org/archives/2022/05/nf-%ce%bab-in-age-related-inflammation-and-immunosenescence/

NF-κB is a well studied player in the complex regulatory systems that control the production and processing of inflammatory signaling in cells. Cells sense their environment and produce inflammatory signals in reaction to prompts, drawing in immune cells to investigate and amplify the local response if necessary. Unfortunately the cell and tissue damage characteristic of aging triggers cells into producing inflammatory signals. The consequent chronic inflammation is disruptive of tissue function throughout the body, contributing to degenerative aging. Sophisticated control over inflammatory signaling, eliminating excess inflammation while allowing necessary inflammatory signaling to proceed, is thus an important goal in the treatment of aging.

It is important to identify connections between seemingly unrelated mechanisms of ageing, or to discover new aspects of ageing biology. One of the master transcriptional regulators at the crossroads of immunity and ageing is nuclear factor kappa B (NF-κB), with its diverse roles implicated in nearly all the hallmarks of ageing. In this mini review, we aim to expose relatively unexplored topics surrounding NF-κB in the spirit of 'leave no stone unturned'. In both the innate and the adaptive immune systems, NF-κB senses danger signals and regulates the expression of cytokines and their receptors in a complex cell-cell communication cascade. Therefore, any age-related intrinsic defects of NF-κB signaling would have a direct impact on cell-cell communications within the immune system and with the surrounding microenvironments.

Here we discuss evidence and ideas for the relevance of NF-κB in two concepts of immune ageing: inflammageing and declining adaptive immunity (immunosenescence). Activated in virtually all cell-cell communication networks of the immune system, NF-κB is thought to affect age-related defects of both innate and adaptive immune cells, relevant to inflammageing and declining adaptive immunity, respectively. Moreover, the family of NF-κB proteins that exist as heterodimers and homodimers exert their function beyond the immune system. Given their involvement in diverse areas such as DNA damage to metabolism, NF-κB has the potential to serve as linkages between known hallmarks of ageing. However, the complexity of NF-κB dimer composition, dynamic signaling, and tissue-specific actions has received relatively little attention in ageing research.