Fight Aging!

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/

Longevity Industry Consulting Services

Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/

Contents

• Year End Charitable Donations to Help Advance Rejuvenation Research
• The Realization that Developing Rejuvenation Therapies is the Most Useful Thing One Can Do with Great Wealth
• Prodrugs As a Useful Approach to Targeting Distinctive Aspects of Cancer Metabolism
• First Generation Stem Cell and Exosome Therapies Promote Neurogenesis
• Studying the Trajectory of Exercise Across Life Suggests that It is Never Too Late to Undertake More It
• Grip Strength Remains a Decent Biomarker of Aging
• TREM2 Associated with Inability of Aged Microglia to Clear Amyloid-β in the Brain
• YAP and TAZ in Cell Structure and Cell Senescence
• A U-Shaped Dose-Response Curve for Resistance Exercise?
• IGF1 Gene Therapy as a Neuroprotective Treatment, Slowing Female Reproductive Aging
• Medin Amyloid May Be Important in Alzheimer's Disease
• Gain or Loss of Specific Microbial Species May Be a Better Measure of Gut Microbiome Aging
• Further Discussion of the Poor Evidence For Metformin to Even Mildly Slow Aging`
• mTOR in the Enhancement of Cancer Treatment Outcomes via Calorie Restriction
• Targeting the Aging of the Immune System in the Context of Frailty

Year End Charitable Donations to Help Advance Rejuvenation Research
https://www.fightaging.org/archives/2022/11/year-end-charitable-donations-to-help-advance-rejuvenation-research/

As Giving Tuesday approaches once again, it is time to consider charitable donations for the end of 2022. If your priority is to reduce human suffering in the world, then by far the most cost-effective approach is to support scientific programs that enable the development of rejuvenation therapies. In comparison to the vast and inflated cost of medicine, the scientific research that produces the means to make new medicines is cheap. Given the right infrastructure of advocacy and networking between the scientific community and industry, new scientific results achieved at low cost can inspire a great deal of investment in further development.

Our community of patient advocates, scientists, fundraisers, and entrepreneurs has spent the past two decades building out that infrastructure: people and organizations that identify the most promising research programs, help to fund them, and then transfer the successful results into venture-funded biotech startups. That ecosystem grows with time, and the original efforts are now spread out over a number of non-profits, collaborating with a network of allied researchers. All of these non-profits merit ongoing philanthropic support, so that they continue to build a pipeline from academia to industry for the most promising approaches to human rejuvenation.

Firstly the SENS Research Foundation, spun out from the Methuselah Foundation, the original starting point for this community. SENS Research Foundation maintains a research group and laboratory that has led to a number of spin-out companies focused on aspects of rejuvenation via damage repair, such as Cyclarity. It further funds research in a number of allied institutions around the world, focused on enabling repair of the cell and tissue damage that causes aging, particularly in parts of the field that appear to be neglected or moving too slowly.

Secondly, Aubrey de Grey's new Longevity Escape Velocity (LEV) Foundation will perform similar work to the SENS Research Foundation, with an initial focus on combining approaches to demonstrate that repairing different forms of cell and tissue damage simultaneously will produce greater, synergistic gains, as expected from a damage-focused view of aging. If you were a supporter of the SENS Research Foundation, you might take a look at the projects that will be undertaken at the LEV Foundation and choose to support both organizations.

Thirdly, the Methuselah Foundation continues to perform a range of important work in the field of rejuvenation research, in combination with an allied venture fund, the Methuselah Fund. The primary focus is tissue engineering and production of replacement organs, but they are also involved in numerous other projects relevant to research into aging and rejuvenation.

The principals at all of these organizations are involved behind the scenes in networking, arranging connections between scientists and entrepreneurs, agitating for specific programs to receive support, and in general trying to move humanity closer to an era in which aging is a medical condition that can be controlled, repaired, reversed. Their actions over the past twenty years have helped bring us to the point at which a longevity biotech industry actually exists, and many formerly languishing research programs have made the leap to preclinical and clinical development.

We live in exciting times! A great deal of work remains to be carried out, however. Many scientific programs necessary to the repair of cell and tissue damage remain poorly funded. If a comprehensive toolkit of rejuvenation therapies is to be produced in our lifetime, something must be done about that. The field moves as fast as we collectively help it to move; science runs on funding as much as it runs on enthusiasm. So pick one of these worthy non-profits and make a donation!

The Realization that Developing Rejuvenation Therapies is the Most Useful Thing One Can Do with Great Wealth
https://www.fightaging.org/archives/2022/11/the-realization-that-developing-rejuvenation-therapies-is-the-most-useful-thing-one-can-do-with-great-wealth/

A core point regarding wealth, realized by many but only acted on by a few to date, is that being the wealthiest individual in the graveyard begins to look very foolish in an era in which research and development is producing the basis for rejuvenation therapies. Historically, people traded time for wealth. Now, we enter the start of the era in which people can trade wealth for time. Fortunately, this is a collaborative venture: no-one wins on their own. Either sufficient funding is devoted to the right projects in rejuvenation biotechnology, and all humanity benefits as a result, or we as a society collectively fail to achieve that goal.

Another important point made in this article is that it is challenging for outsiders to make sense of a field of endeavor in which half of the participants appear, on the surface at least, to be modernized versions of 1970s snake oil supplement salespeople, along with a good scattering of eccentric or fraudulent larger than life characters, as well as unhelpful ventures that are clearly chasing or talking up the hype of a longevity industry while providing nothing of any great value.

How does a layperson pick out the legitimate, exciting science of rejuvenation, such as senolytic therapies, or epigenetic reprogramming, from the garbage that is discussed and marketed in exactly the same terms? Eventually the good drives out the bad, but for now we're still stuck with a mess of alchemists pretending to be scientists, alongside supplement salespeople making hay while the sun shines, siphoning attention and funding away from actually valuable projects.

Inside the billion meeting for the mega-rich who want to live forever

The super-rich eventually reach a point where having more money doesn't improve their lives very much. "If you buy a yacht, you can always get a bigger yacht; if you buy a plane, you can always get a bigger plane. But the extent to which your life is changing with more money is actually very minimal." It makes more sense to direct funds to being healthier and living longer. Such deep-pocketed individuals and groups are looking to be the biggest investors in longevity research. Most of the 4.4 billion invested over the last five years into understanding whether or not reprogramming our cells might help us live longer has gone into Altos Labs, a biotech company whose funders are thought to include Jeff Bezos and Yuri Milner.

A sense of hope and optimism was palpable at the Longevity Investors Conference. I got the impression that most people believed that, with enough funding, positive scientific results were just a few years away. And with that, we'd be on the road to reliably extending human healthspan. The presenters were a mix of longtime academics, biotech startups, and people selling the idea of longevity as a high-end luxury good for those who frequent spas and lavish retreats. Some have been studying the biology of aging for decades, and are well-respected among their peers. But I also met a young man who told me that breathing low-oxygen air could benefit multiple aspects of my health - and who then commented that he "didn't believe" in covid vaccines. A 67-year-old man took to the stage to tell us that, since he'd been taking his own supplement, his biological age had reversed, and he was now biologically only 49 years old.

How is an investor - or anyone else, for that matter - meant to make sense of all these claims? Ask an academic, and they'll tell you that the answer is education-the more people know about the biology of aging and how clinical trials work, the better placed they are to work out how much faith to put in any claim. Many agree that it's the wild claims made by some - claims that we could live to be a thousand years old, or avoid death entirely - that have helped bring attention and investment to the field. But they have also tarnished its reputation as a scientific discipline.

Others say that while there's more hype in biotech than academia, they thinks that any hype tends to be short-lived. "If you're selling hot air, you can't get away with doing that for very long." I've been writing about the science of aging for over a decade myself, and I'm not sure I fully agree with him. I've seen shoddy science get plenty of press attention. I've seen smart scientists fall prey to flimsy claims about health-extending supplements. But I've also seen some fascinating and tantalizing research - enough to want to follow it through and find out if these approaches really will be as beneficial for people as they are for lab animals.

Prodrugs As a Useful Approach to Targeting Distinctive Aspects of Cancer Metabolism
https://www.fightaging.org/archives/2022/11/prodrugs-as-a-useful-approach-to-targeting-distinctive-aspects-of-cancer-metabolism/

The goal of cancer research should be to produce a robust, highly effective universal cancer therapy, or as close to universal as possible. One treatment that can be deployed for every type of cancer, with a very good chance of inducing remission. Attempting to tackle cancer subtypes one by one based on their genetic peculiarities is simply not efficient enough to produce meaningful progress in our lifetimes. Further, most cancers are subject to high mutation rates, and in a sizable fraction of patients will prove to be quite capable of evolving immunity to any therapy that targets a non-essential aspect of cancer biochemistry.

Cancer cells as a class are metabolically very different from normal cells; they have to be in order to power the rampant growth characteristic of tumor tissue. This presents a broad area of discovery for the development of prodrugs, molecules in which a toxic drug is amended to become non-toxic in a way that can be reversed by the activity of enzymes present only in the the targeted cell populations. This in principle allows for any usefully toxic chemotherapeutic drug, of which there are many, to be amended into a non-toxic form that will be near entirely processed back into the original toxic drug only by cancer cells. Importantly, at least some prodrug strategies of this nature might be applicable to a broad range of cancers.

Researchers Design 'Prodrug' That Targets Cancer Cells' Big Appetite for Glutamine, Leaving Healthy Cells Unharmed

"Our goal was to modify an old cancer drug that had shown robust efficacy but was too toxic, especially to the gut, to be developed clinically. To do this, we used a prodrug approach." The newly modified prodrug takes advantage of a common property of cancer cells: a voracious appetite for an amino acid called glutamine, which is a critical building block for proteins, lipids, and nucleotides, as well as for energy formation. Rapidly growing cancer cells use a tremendous amount of glutamine, a phenomenon called "glutamine addiction," but other healthy cells with rapid turnover, like those lining the gut, also rely on glutamine.

"DRP-104 is a tumor-targeted prodrug of the glutamine mimic drug called DON (6-Diazo-5-Oxo-L-norleucine), which inhibits multiple glutamine-utilizing enzymes in cancer cells. Many early studies of DON showed it was robustly efficacious in people and mice, but its development was halted due to its toxicity to normal tissues, especially the gut. We added chemical groups, called promoieties, to DON that rendered it inactive in the body until it reached the tumor, where the promoieties were clipped off by enzymes that are abundant in the tumor but not in the gut."

Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues.

In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

First Generation Stem Cell and Exosome Therapies Promote Neurogenesis
https://www.fightaging.org/archives/2022/11/first-generation-stem-cell-and-exosome-therapies-promote-neurogenesis/

First generation stem cell transplants have not as yet produced the reliably improved regeneration that was hoped for, but they do suppress chronic inflammation for some months. This effect is mediated by cell signaling on the part of the transplanted cells in the short time that they survive after transplantation. Much of that signaling is carried by exosomes and other classes of extracellular vesicle, and hence similar outcomes result from therapies based on delivery of exosomes harvested from cultured stem cells.

One of the effects of the unresolved inflammatory signaling characteristic of aging is a suppression of stem cell activity, such as in the cell populations responsible for producing new neurons in the brain. Neurogenesis is essential to brain maintenance, as well as memory and learning. From what is known to date, greater neurogenesis appears to be beneficial at any age. Thus one of the ways in which first generation stem cell and exosome therapies might act to improve cognitive function in older people is via suppression of inflammation leading to improved neurogenesis in the aging brain.

Mesenchymal stem cells and exosomes improve cognitive function in the aging brain by promoting neurogenesis

Brain aging is a significant cause of most neurodegenerative diseases and is often irreversible and lacks an effective treatment, leading to a dramatic decline in quality of life. As with other organ systems, brain function gradually declines during the aging, mainly in learning and memory functions. Some studies point out that age-related cognitive decline is characterized by a considerable reduction or even death of neurons in the brain. In the hippocampus (and perhaps in other brain areas), neuronal death can partially compensated by neuronal generation. However, neuronal production is significantly impaired with age. In the adult mammalian hippocampus, new neurons are derived from the stem cell and progenitor cell divisions, a process known as adult neurogenesis.

In recent years, evidence has accumulated that neurogenesis can restore a more youthful state during aging. In addition, increased adult neurogenesis contributes to a variety of human diseases, including cognitive impairment and neurodegenerative diseases. Neuroinflammation has been shown to alter neurogenesis in adults. Various inflammatory components, such as immune cells, cytokines, or chemokines, regulate neural stem cells' survival, proliferation, and maturation. During normal brain aging, increased inflammatory activity is caused by the activation of glial cells.

It has been shown that mesenchymal stem cells (MSCs) can stimulate neurogenesis and angiogenesis and delay neuronal cell death. At the same time, their secreted exosomes are smaller in size and cause less immune response in the body, which is a hot topic of current research. This manuscript describes how MSCs and their derived exosomes promote brain neurogenesis and thereby delay aging by improving brain inflammation.

Studying the Trajectory of Exercise Across Life Suggests that It is Never Too Late to Undertake More It
https://www.fightaging.org/archives/2022/11/studying-the-trajectory-of-exercise-across-life-suggests-that-it-is-never-too-late-to-undertake-more-it/

You may recall a study from a few years back suggesting that increasing level of exercise in later life, after a low level of exercise in earlier life, removes a perhaps surprisingly large fraction of the negative consequences of that low level of exercise. This is at least the case when it comes to age-related mortality. Nonetheless, in that study, maintaining a high level of exercise across life was still shown to be much better for health than only beginning high levels of exercise in later life.

Today's open access paper reports on a similar study, but here the metrics are specifically focused on measurements of frailty, such as grip strength. The interesting portion of the outcome is that the people who moved from low levels of exercise to greater exercise look similar to those that always maintained that higher level of exercise. The conclusion that one could make from this is that frailty as presently observed in the wealthier parts of the world is a large part a consequence of inactivity, and that at least that portion of the problem is reversible given sufficient effort.

Associations of physical activity participation trajectories with subsequent motor function declines and incident frailty: A population-based cohort study

Increasing evidence reports the benefits yielded by regular physical activity (PA) on the motor function in older people by preserving mobility, muscle strength, and balance. However, there is a methodological limitation that PA are evaluated at single time-point (primarily the baseline level) or short time-scales without considering the long-term dynamic nature of PA behavior. Group-based trajectory modeling (GBTM) allows grouping of subjects presenting with similar baseline values and longitudinal patterns of change according to their direction and magnitude. Using this method, some studies have detected different PA trajectories among older adult cohorts. Three studies examined the association of PA trajectories with mortality in older adults. But, there isn't an investigation of the temporal association of long-term PA participation trajectories with subsequent motor function changes and incident frailty.

Therefore, the main objectives of this study were to investigate different trajectories of long-term PA participation over a 6-year span by the GBTM and evaluate their associations with subsequent motor function decline and incident frailty in middle-aged and elderly adults. Our hypotheses are that older adults maintaining PA over time will have a slower motor function decline and a lower risk of incident frailty compared with persistently inactive subjects or those reducing PA levels, and that increasing PA even at older ages promotes healthy aging characterized by reduced motor function decline and incident frailty.

Five distinct trajectories of long-term PA participation were identified in the aging cohort, including persistently low-active trajectory (N = 2,039), increasing active trajectory (N = 1,711), declining active trajectory (N = 216), persistently moderate-active trajectory (N = 2,254), and persistently high-active trajectory (N = 2,007). Compared with the persistently low-active group, the participants in persistently moderate- and high-active groups experienced significantly decelerated grip strength decline, decreased gait speed decline, and faster chair rises after multiple-adjustment. Similarly, participants maintaining moderate- and high-active PA were also associated with a lower risk of incident frailty (multiple-adjusted hazard ratio 0.70 and 0.42 respectively), compared with those with persistently low PA. Notably, the participants with the increasing active trajectory got similar health benefits as those with persistently moderate and high levels of PA.

Thus in conclusion, in addition to persistent PA, increasing PA was linked to a slower decline in motor function and lower risk of incident frailty in the cohort. Our findings suggest that regular PA is never too late.

Grip Strength Remains a Decent Biomarker of Aging
https://www.fightaging.org/archives/2022/11/grip-strength-remains-a-decent-biomarker-of-aging/

Of the various simple measures that correlate with mortality and risk of age-related disease, grip strength remains a relatively good option, even in this modern era of epigenetic clocks. Illustrative of this point, researchers here show a correlation between grip strength and epigenetic age data in a sizable study population. The degree to which an individual suffers from the chronic inflammation of aging may be an important determinant of this relationship. Inflammation disrupts tissue function throughout the body, and maintenance of muscle mass and strength is one of the aspects of health negatively affected by unresolved inflammatory signaling.

Researchers modeled the relationship between biological age and grip strength of 1,274 middle aged and older adults using three "age acceleration clocks" based on DNA methylation, a process that provides a molecular biomarker and estimator of the pace of aging. The clocks were originally modeled from various studies examining diabetes, cardiovascular disease, cancer, physical disability, Alzheimer's disease, inflammation, and early mortality. Results reveal that both older men and women showed an association between lower grip strength and biological age acceleration across the DNA methylation clocks. The real strength of this study was in the eight to 10 years of observation, in which lower grip strength predicted faster biological aging measured up to a decade later.

Past studies have shown that low grip strength is an extremely strong predictor of adverse health events. One study even found that it is a better predictor of cardiovascular events, such as myocardial infarction, than systolic blood pressure - the clinical hallmark for detecting heart disorders. Researchers have previously shown a robust association between weakness and chronic disease and mortality across populations. This evidence coupled with the recent findings shows potential for clinicians to adopt the use of grip strength as a way to screen individuals for future risk of functional decline, chronic disease and even early mortality.

Future research is needed to understand the connection between grip strength and age acceleration, including how inflammatory conditions contribute to age-related weakness and mortality. Previous studies have shown that chronic inflammation in aging - known as "inflammaging" - is a significant risk factor for mortality among older adults. This inflammation is also associated with lower grip strength and may be a significant predictor on the pathway between lower grip strength and both disability and chronic disease multimorbidity.

TREM2 Associated with Inability of Aged Microglia to Clear Amyloid-β in the Brain
https://www.fightaging.org/archives/2022/11/trem2-associated-with-inability-of-aged-microglia-to-clear-amyloid-%ce%b2-in-the-brain/

TREM2 has become a gene of interest in Alzheimer's research, particularly now that a greater focus is given to chronic inflammation, and other aspects of immune aging, in the development and progression of this and other neurodegenerative conditions. TREM2 is a receptor that mediates the ability of microglia, innate immune cells of the brain, to take up and clear amyloid-β aggregates from the brain. Targeting TREM2 with antibodies appears to improve the ability of microglia to perform this task. Absent this sort of intervention, however, microglia in aged individuals both lose TREM2 expression and become less capable of amyloid-β clearance.

Age-associated microglial dysfunction contributes to the accumulation of amyloid-β (Aβ) plaques in Alzheimer's disease. Although several studies have shown age-related declines in the phagocytic capacity of myeloid cells, relatively few have examined phagocytosis of normally aged microglia. Furthermore, much of the existing data on aging microglial function have been generated in accelerated genetic models of Alzheimer's disease. Here we found that naturally aged microglia phagocytosed less Aβ over time. To gain a better understanding of such dysfunction, we assessed differences in gene expression between young and old microglia that either did or did not phagocytose Aβ.

Young microglia had both phagocytic and neuronal maintenance signatures indicative of normal microglial responses, whereas, old microglia, regardless of phagocytic status, exhibit signs of broad dysfunction reflective of underlying neurologic disease states. We also found downregulation of many phagocytic receptors on old microglia, including TREM2, an Aβ phagocytic receptor. TREM2 protein expression was diminished in old microglia and loss of TREM2+ microglia was correlated with impaired Aβ uptake, suggesting a mechanism for phagocytic dysfunction in old microglia. Combined, our work reveals that normally aged microglia have broad changes in gene expression, including defects in Aβ phagocytosis that likely underlies the progression to neurologic disease.

YAP and TAZ in Cell Structure and Cell Senescence
https://www.fightaging.org/archives/2022/11/yap-and-taz-in-cell-structure-and-cell-senescence/

This scientific commentary describes an interesting join the dots exercise in which scientists link together a number of different topics that have shown up over the years in research into aging. Here, the Hippo pathway (activated by YAP and TAZ), the shape and maintenance of the nuclear envelope, inflammatory cGAS/STING signaling, and cellular senescence are all connected. Declining expression of YAP and TAZ occur with aging, for reasons to be explored, and that decline appears sufficient in and of itself to trigger the rest of the linked cascade of changes and consequent cellular senescence and tissue dysfunction.

A recent study tested the possibility that altered mechanosensing of the extracellular environment, i.e., the extracellular matrix (ECM), is a signal for physiological aging. The transcriptional coactivators and end effectors of the Hippo signaling pathway, YAP and TAZ, are established mediators that link mechanosensation to changes in cell behavior through the regulation of transcriptional programs.

To explore the hypothesis that YAP/TAZ mediate effects of aging, the authors first performed a series of experiments employing single-cell RNA-seq data that indicated the downregulation of a YAP/TAZ activation signature gene set in dermal fibroblasts of old mice. This pattern of depressed YAP/TAZ activity was also observed in other stromal cells (e.g., kidney fibroblasts) as well as contractile cells (cardiomyocytes, vascular smooth muscle cells) but not in epithelial cells, hepatocytes, or lymphocytes, indicating cell-type specificity.

Depletion of YAP/TAZ in young mice reduced dermal fibroblast number and phenocopied aged skin in control mice. Targeted deletion of YAP/TAZ in vascular smooth muscle cells elicited aortic dissection, rupture, and death in several weeks, thereby accelerating aging-associated pathology. To further substantiate YAP/TAZ regulation of cellular senescence, transcriptome profiling in freshly isolated dermal fibroblasts from young mice demonstrated increased senescence-associated secretory phenotype (SASP) genes as well as increased β-gal expression, both hallmarks of senescence, in YAP/TAZ deficient cells. On the other hand, supplementing YAP to fibroblasts cultured from old mice led to suppression of SASP and β-gal positivity.

cGAS-STING signaling modulates innate immune responses and has been previously implicated in the regulation of senescence. Through multiple complementary approaches, researchers showed that YAP/TAZ suppressed cGAS activation in several cell and tissue types, and involved the inappropriate release of genomic DNA into the cytosol. How does YAP/TAZ restrain cGAS-STING? The authors astutely recognized a relationship between decreased YAP/TAZ activity and distorted nuclear architecture in old cells. Moreover, the addition of active YAP rescued abnormal nuclear structure caused by aging. Additional screens revealed that YAP/TAZ directly promote the expression of two key factors that maintain proper nuclear envelope integrity, lamin B1 and ACTR2.

These findings demonstrate that YAP/TAZ is a critical upstream modulator of nuclear integrity and functions in young cells to keep cGAS-STING in check to prevent the aging phenotype of cellular senescence.

A U-Shaped Dose-Response Curve for Resistance Exercise?
https://www.fightaging.org/archives/2022/11/a-u-shaped-dose-response-curve-for-resistance-exercise/

A fair number of studies have shown reduced late life mortality to correlate with, or result from, programs of resistance exercise. While a great many studies of aerobic exercise have indicated that at very high levels of exercise there is increased mortality versus more modest programs of exertion, in other words that the dose-response curve is U-shaped, it isn't completely clear that this is also the case for resistance exercise. While a fair number of studies have taken place, there isn't as much evidence to assess. This short paper provides a high level discussion of the present state of knowledge and some references to follow up on for those interested in the details.

Regular physical activity (PA) promotes healthy aging, and activities aiming to increase muscular strength (i.e., resistance exercise, RE) are important PA modalities for achieving health benefits. Previous meta-analyses demonstrated that both RE and muscular strength were associated with mortality benefits, even when RE was performed above the PA targets recommended by current guidelines.

While optimal volumes of endurance-type exercise (aerobic moderate-to-vigorous PA, MVPA) to reduce mortality from all causes have been suggested to amount to or even exceed 700 minutes per week, recent meta-analyses suggest that large amounts of RE may be associated with adverse outcomes. Although these analyses demonstrated an overall inverse association between RE and mortality risk from all causes and/or from cardiovascular diseases (CVD), diabetes, and cancers, this was only true up to a certain threshold of RE volume per week (i.e., there is a U-shaped dose-response relationship between RE and mortality). Should the many individuals engaging in RE volumes exceeding the reported cutoffs for optimal benefits be worried?

Overall, excessive RE may put a small number of individuals at a higher risk for adverse health outcomes, which is similar to the effect of extreme endurance exercise. This risk may vary with age and sex (e.g., while young subjects may be more susceptible than older ones to arterial stiffness following RE, men are much more likely than women to be injured performing RE) and can increase with inappropriate execution of RE, overconfidence, and/or subtle pre-existing comorbidities.

Although low-to-moderate intensity RE is usually well tolerated and widely recommended for individuals with and without cardiovascular disease, heart rate and systolic blood pressure values in cardiac patients are higher during low-intensity as compared to high-intensity RE. As low-intensity RE is typically performed at higher volumes than high-intensity RE, vulnerable individuals performing high volumes of low-intensity RE might be at higher mortality risk than previously assumed.

IGF1 Gene Therapy as a Neuroprotective Treatment, Slowing Female Reproductive Aging
https://www.fightaging.org/archives/2022/11/igf1-gene-therapy-as-a-neuroprotective-treatment-slowing-female-reproductive-aging/

Researchers here describe an interesting approach to slowing aspects of neurodegeneration that contribute to, among other things, female reproductive aging. That is the focus of this paper, but numerous other aspects of the aging brain are also involved. IGF1 is well studied in the context of aging, and manipulation of the signaling pathways linking insulin, IGF1, and growth hormone has been shown to extend life span in a number of species. Where we can make direct comparisons between mice and humans, such as between growth hormone receptor knockout mice and humans with Laron syndrome, the effects are nowhere near as large. Suppression of growth hormone signaling can extend life by 70% or so in mice, but Laron syndrome doesn't appear to make humans live meaningfully longer. Many approaches to slowing aging have much larger effects in short-lived mammals than they do in long-lived mammals.

The inflammatory environment characteristic of the aged brain is caused by activation of glial cells, mainly microglia. Several studies report that neuroinflammation leads to reduced gonadotropin-releasing hormone (GnRH) secretion, which is associated with multiple aging-related physiological changes, including bone loss, skin atrophy, muscle weakness, and memory loss. Indeed, GnRH administration amend aging-impaired neurogenesis and decelerates aging in mice. In addition, the same authors also describe that inhibition of NF-κB-directed immunity, specifically in hypothalamic microglia cells, has an anti-aging effect.

GnRH secretion is regulated by hormonal and environmental signals such as kisspeptin. This peptide plays a critical role in controlling the onset of puberty and reproductive function in adulthood. There are two populations of kisspeptin neurons, one in the anteroventral periventricular nucleus (AVPV) and one in the arcuate nucleus (Arc), that are targets of positive and negative feedback regulation of estrogen, respectively. Aging female rats transition from regular to irregular estrus cycles, constant estrus, and finally to an anestrus stage. Changes within the hypothalamic-pituitary-ovarian axis, manifested by altered secretion of neurotransmitters, altered secretion of pituitary hormones and altered follicular development and steroid content, lead to the final cessation of reproductive cycles. These processes that lead to reproductive senescence are associated with an increase in circulating cytokines and proinflammatory markers produced by microglial cells. Indeed, several studies describe that hypothalamic and systemic inflammation affect kisspeptin neurons, which are responsible for regulating GnRH neurons.

IGF1 is a neurotrophic factor with an outstanding neuroprotective action in the central nervous system. Previous studies of our group showed that intraparenchymal hypothalamic IGF1 gene therapy was capable to prolong the operation of reproductive cycles in rats. Indeed, we have demonstrated that intracerebroventricular IGF1 gene therapy restores motor performance and generates cognitive and morphological changes in the dorsal hippocampus in senile rats. In addition, we have reported that IGF1 gene therapy modifies microglia number and phenotype in senile rats and decreases astrocytic inflammatory response in vitro, supporting the extensive idea that IGF1 plays a potent anti-inflammatory effect.

The aim of the present study is to investigate the effect of IGF1 gene therapy on estrous cycle, kisspeptin, and GnRH neurons, and microglial cells in middle-aged female rats. Our data indicate that IGF1 gene therapy prolongs the operation of reproductive cycles in middle-aged rats by modulating kisspeptin/GnRH secretion in the hypothalamus and altering microglial cell number and reactivity. Based on our findings, we propose IGF1 gene therapy to delay reproductive senescence as a potential strategy to optimize lifespan and combat age-related health problems in women.

Medin Amyloid May Be Important in Alzheimer's Disease
https://www.fightaging.org/archives/2022/11/medin-amyloid-may-be-important-in-alzheimers-disease/

There are a score or so of proteins in the human body capable of producing amyloid when they misfold, by encouraging other molecules of the same protein to misfold in the same way, linking together to produce solid deposits in and around cells. Only those amyloids for which there is clear evidence of disease association or toxicity to cells have been well studied, unfortunately. That doesn't mean that the others are harmless! As demonstrated here, it may just be the case that researchers have to look a little harder to find the ways in which these amyloids are causing pathology in older people.

Medin belongs to the group of amyloids. Of these proteins, amyloid-β is best known because it clumps together in the brains of Alzheimer's patients. These aggregates then deposit both as so-called plaques directly in the brain tissue, but also in its blood vessels, thereby damaging the nerve cells and the blood vessels, respectively. But while many studies have focused on amyloid-β, medin has not been a focus of interest.

However, medin is actually found in the blood vessels of almost everybody over 50 years of age, making it the most common amyloid known. Medin even develops in aging mice. The older the mice get, the more medin accumulates in the blood vessels of their brains. What's more, when the brain becomes active and triggers an increase in blood supply, vessels with medin deposits expand more slowly than those without medin. This ability of blood vessels to expand, however, is important to optimally supply the brain with oxygen and nutrients.

Now researchers were able to show in Alzheimer's mouse models that medin accumulates even more strongly in the brain's blood vessels if amyloid-β deposits are also present. Importantly, these findings were confirmed when brain tissue from organ donors with Alzheimer's dementia was analysed. However, when mice were genetically modified to prevent medin formation, significantly fewer amyloid-β deposits developed, and as a result, less damage to blood vessels occurred. "There are only a handful of research groups worldwide working on medin at all. We have now been able to show through many experiments that medin actually promotes vascular pathology in Alzheimer's models, and this indicates that medin is one of the causes of the disease."

Gain or Loss of Specific Microbial Species May Be a Better Measure of Gut Microbiome Aging
https://www.fightaging.org/archives/2022/11/gain-or-loss-of-specific-microbial-species-may-be-a-better-measure-of-gut-microbiome-aging/

It now costs little to determine the contents of the gut microbiome, producing a list of microbial species and their prevalence. Numerous companies offer this service. This data can be sliced in numerous ways, but as researchers note here, it is the gain and loss of specific populations with advancing age that produces contributions to aging. More general measures of diversity or change, those that give little to no weight to which specific microbial populations alter in abundance, do not produce good correlations with degenerative aging. It is important to consider the actions and mechanisms of specific microbes: are they causing chronic inflammation, are they generating beneficial or harmful metabolites, and so forth.

The gut microbiome is a modifier of disease risk because it interacts with nutrition, metabolism, immunity, and infection. Aging-related health loss has been correlated with transition to different microbiome states. There is broad consensus how the microbiome changes with age, but specific intervention targets are less clear. Moreover, terms like diversity, assumed by many to be desirable, and 'uniqueness', which has been cast as a marker of healthy aging, need greater precision and should not be used agnostic of the loss or gain of specific taxa in aging. Other summary statistics include different measures of uniqueness that capture specific aspects of gut microbiome variability and are calculated using different distance measures.

This study explored whether determining the gain or loss of specific taxa represent a more precise metric of healthy/unhealthy aging than summary microbiome statistics, such as diversity and uniqueness. We analyzed microbiome diversity and four measures of microbiome uniqueness in 21,000 gut microbiomes for their relationship with aging and health. We show that diversity and uniqueness measures are not synonymous; uniqueness is not a uniformly desirable feature of the aging microbiome, nor is it an accurate biomarker of healthy aging. Different measures of uniqueness show different associations with diversity and with markers of health and disease.

The study identifies that the gut microbiome alterations associated with both aging in general and unhealthy aging are characterized by a common theme: loss of the core microbiome structure (specifically a coabundant species-level guild of the core microbiome) and concomitant increase of a specific guild of disease-associated taxa.

Further Discussion of the Poor Evidence For Metformin to Even Mildly Slow Aging`
https://www.fightaging.org/archives/2022/11/further-discussion-of-the-poor-evidence-for-metformin-to-even-mildly-slow-aging/

The problem with metformin as a drug to slow aging is that the evidece to support that use is very poor. In animal studies, the results are very unreliable, and the Interventions Testing Program found no effect in its highly overengineered studies. Further, the existing human data is not supportive, taken as a whole. Even if we did want to cherry pick the better data and be hopeful, the effect size compares unfavorably with that achieved through regular exercise, and further appears to be only achieved in people with the abnormal metabolism associated with obesity and diabetes. All of the work that was done to convince the FDA to endorse the TAME human clinical trial to test the ability of metformin to slow aging is useful, but the resulting agreement on trial structure should be applied to an intervention more likely to produce an outcome that is worth the effort, such as senolytic therapies.

The study that is most often cited as evidence that metformin slows the aging process in humans was released with a press release misleadingly titled "Type 2 diabetics can live longer than people without the disease." But the underlying study had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients with poorer glycemic control (those on other drugs) and a random assortment of the nondiabetic population - and then systematically pushed subjects on metformin "off the books" as soon as their diabetes progressed.

The same problem (or related ones) have plagued most of the observational studies that you may have heard cited as showing that metformin lowers the risk of atherosclerosis, total mortality, and especially cancer. Drawing inferences from such studies about effects on aging in otherwise-healthy people would thus be misguided even if these studies didn't share this design flaw, since none of these other studies include a separate group of people without diabetes. Rather, such studies have compared metformin-taking diabetic people to other people with diabetes taking other diabetic drugs. But actually, even in such diabetics-only studies, the apparent benefits of metformin vanish when the studies are designed to avoid survivorship bias and selection bias.

When put to the test in human trials, metformin has no effect on blood sugar control in obese women with normal glucose tolerance and only modest effects on fasting glucose in normal-weight, nondiabetic men. Similarly, exercise but not metformin tames glycemic variability (dangerously wide swings in blood sugar over the course of the day) in prediabetic people. And importantly, adding metformin to such lifestyle interventions doesn't lower the risk of developing diabetes any more than lifestyle all by itself.

You may be surprised to learn that there has already been a trial with followup that gives fairly long-term human data on mortality in a group of people who were not yet diabetic - and again, metformin came up short. This was report from the long-term follow-up of the Diabetes Prevention Program (DPP). The volunteers in the DPP were on average 50 years old, and all had prediabetes. The DPP itself lasted only 2.8 years, but the researchers followed up with the participants at 10, 15, and as much as 20 years later. And to get to the punchline, people who had been taking metformin lived no longer than people in the control group.

mTOR in the Enhancement of Cancer Treatment Outcomes via Calorie Restriction
https://www.fightaging.org/archives/2022/11/mtor-in-the-enhancement-of-cancer-treatment-outcomes-via-calorie-restriction/

Calorie restriction, and related approaches such as protein restriction, tend to improve the outcomes for cancer patients, making cancers more vulnerable to therapies by reducing the normally rampant replication of cancer cells. Here, researchers explore the role of mTOR signaling in the mechanisms underlying this effect, finding the link between dietary intake of amino acids and mTOR activity in cell growth. Manipulating these mechanisms isn't enough on its own to deal with cancer, but there is a lot to be said for low cost improvements to the odds of success for patients undertaking any form of cancer therapy.

Researchers found in cells and in mice that a low-protein diet blocked the nutrient signaling pathway that fires up a master regulator of cancer growth. The regulator, mTORC1, controls how cells use nutritional signals to grow and multiply. It's highly active in cancers with certain mutations and is known to cause cancer to become resistant to standard treatments. A low-protein diet, and specifically a reduction in two key amino acids, changed the nutritional signals through a complex called GATOR.

GATOR1 and GATOR2 work together to keep mTORC1 in business. When a cell has plenty of nutrients, GATOR2 activates mTORC1. When nutrients are low, GATOR1 deactivates mTORC1. Limiting certain amino acids blocks this nutrient signaling. Previous efforts to block mTORC1 have focused on inhibiting its cancer-causing signals. But these inhibitors cause significant side effects - and when patients stop taking it, the cancer comes back. The study suggests that blocking the nutrient pathway by limiting amino acids through a low-protein diet offers an alternative way to shut down mTORC1.

Researchers confirmed their findings in cells and mice, where they saw that limiting amino acids stopped the cancer from growing and led to increased cell death. They also looked at tissue biopsies from patients with colon cancer, which confirmed high markers of mTORC correlated with more resistance to chemotherapy and worse outcomes.

Targeting the Aging of the Immune System in the Context of Frailty
https://www.fightaging.org/archives/2022/11/targeting-the-aging-of-the-immune-system-in-the-context-of-frailty/

The immune system declines into a state of incapacity (immunosenescence) and chronic inflammation (inflammaging) with advancing age. Unresolved inflammatory signaling is disruptive of tissue function in many ways, from reduced stem cell activity to pathologically altered somatic cell behavior. It is thought to be important in the declining muscle mass and strength that contributes to age-related frailty. Thus addressing immune aging is a significant and important target in the treatment of aging as a whole.

Frailty is a highly prevalent geriatric syndrome that has attracted significant attention from physicians and researchers due to its associated increase in vulnerability and healthcare costs, especially in the elderly population. Generally, frail patients suffer from multiple chronic diseases, with comorbidities and polypharmacy greatly challenging their health management. Gerontologists suggest that targeting the common pathogenesis of comorbidities rather than a single disease is probably a better solution for older people. Multiple factors contribute to development of frailty with advancing age, thus the therapeutic target is diversed depends on specific condition. Nutrition supplements and physical exercise are proved to be helpful in preventing and treatment of frailty, however, valid pharmaceutical intervention is scarce.

Mesenchymal stem cells (MSCs) can exert regenerative effects and possess anti-inflammatory properties, offering a promising therapeutic strategy to address the pathophysiologic problems of frail syndrome. Currently, MSC therapy is undergoing phase I and II trials in human subjects to endorse the safety and efficacy of MSCs for aging frailty.

Numerous studies have shown that rapamycin and rapalogs, considered novel and promising longevity agents, can extend lifespan. Interestingly, these agents showed an immunosuppressive effect at high doses and an immune stimulatory effect at low doses. However, the reason for these immunity-boosting effects is unclear. The inhibition of mammalian target of rapamycin (mTORC1) is a possible explanation, as mTOR can regulate the STAT signaling pathway. A study showed a significant difference in STAT phosphorylation levels in the T cells of healthy people compared with unhealthy senescent people.

Senolytics are a novel type of agent. The interference of stem cell signaling pathways temporarily disables the senescent cell anti-apoptotic pathway (SCAP), thus targeting selectively senescent cells. In addition to its main effect on clearing senescent cells, senolytics can also eliminate pro-inflammatory cytokines. According to the study, inflammation symptoms are relieved after the administration of senolytics. A recent study found reduced SASP and coronavirus-related mortality in old mice after the administration of senolytics.

A low level of nicotinamide adenine dinucleotide (NAD)+ is reportedly associated with the poor function of mitochondria and metabolic reprogramming of immune cells; therefore, NAD+ is also recognized as a therapeutic target for aging immunity. Promising data has demonstrated that administrating nicotinamide mononucleotide, the NAD+ precursor, into mice could maintain NAD+ levels and mitochondrial function, with the mitochondrial function of immunocytes being essential for controlling virus propagation.

A centenarian study revealed that longevity is associated with gut microbial structures, making individuals more potent against age-associated disorders and leading to a longer life. The microbiota-targeting probiotic and dietary interventions affect natural aging by enhancing oxidation resistance, regulating metabolism, suppressing chronic inflammation, and promoting immune homeostasis. Immunosenescence may have a certain influence on human microbial composition, function, and diversity. In addition, fecal microbiota transplantation or prebiotic/probiotic/synbiotic supplementation in the diet is beneficial for restoring active microbiota and extending a healthy lifespan. Thus, there are multiple ongoing developments in this field to ease the process of aging and reduce the risk of potential disabilities that could lead to a significant decrease in the quality of life of elderly individuals.