Fight Aging!

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Contents

• Degenerative Aging as a Side Effect of the Colonization of Land
• Considering Mechanistic Links Between Vascular Calcification and Osteoporosis
• Present Calorie Restriction Mimetics are a Poor Substitute for the Practice of Calorie Restriction
• AMPK Activator O304 as an Exercise Mimetic Drug
• Like Elephants, Long-Lived Galapagos Tortoises Exhibit Duplication of Genes Related to Longevity and Cancer Suppression
• Live Longer World, Podcast Interviews and Newsletter
• Dogs Benefit from Time Restricted Feeding
• Notes on the Recent Longevity Week in London
• Exercise Delays T Cell Population Aging
• Heterochronic Parabiosis Reduces Epigenetic Age in Mice
• A Narrow Window for Exercise to Improve Neurogenesis via Growth Hormone in Aged Mice
• Modulation of the Aged Gut Microbiome to Benefit Health is a Field in its Infancy
• In Type 2 Diabetes, Arterial Stiffening Causes Increased Structural Damage to the Brain
• Evidence that Metformin Does Not Interfere in the Beneficial Response to Exercise
• Macrophages Essential to Limb Regeneration in the Axolotl Emerge from the Liver

Degenerative Aging as a Side Effect of the Colonization of Land
https://www.fightaging.org/archives/2021/11/degenerative-aging-as-a-side-effect-of-the-colonization-of-land/

Today's open access paper makes for an interesting companion piece to the recently proposed adaptive-hitchhike model for the evolution of longevity. Here also, the length of species life spans and the degree to which age-related degeneration (senescence) takes place over time is suggested to be a side-effect of adaptations to specific ecological niches. The authors of this paper observe that a greater proportion of marine clades have a long life span and lesser degrees of senescence than is the case for land-dwelling clades. Further, a greater fraction of marine species continually grow throughout life, a capability that has implications for the processes of regeneration and tissue maintenance. In addition, species that evolved a return to marine life, such as aquatic mammals, tend to be longer lived than their near relative species that remained land-dwelling.

The paper provides a great deal of data and sorting of that data, but is light on detailed conclusions. It is interesting to see the clear advantage in life span enjoyed, on average, by marine species. It is already the case that many in the research community look at the existence of multiple unusually long-lived species in specific niches, such as naked mole-rats and near relative species in their oxygen-poor underground environment, and hypothesize that longevity arises as a side-effect of the evolutionary adaptations required to thrive in that environment. The work here provides much more food for thought on this topic, to be taken up by molecular biologists in search of compelling mechanisms to explain the observed data on life span, senescence, and ecological niche.

Senescence as a trade-off between successful land colonisation and longevity: critical review and analysis of a hypothesis

Our analysis of the maximum life expectancy of species belonging to the groups of animals revealed distinct groups. The first group was insects, with a 99% share of short-lived species. The second group consisted of amphibians and terrestrial reptiles, with an average maximum life expectancy of about 10 years, though some animals, such as olm (Proteus anguinus), show extremely high life expectancy. The third group consisted of land mammals and some birds. The average life expectancy of animals in these groups is approximately 15 years. Only humans (Homo sapiens) and few other species can be classified as long-lived. The next group comprised of about 20% long-lived species that live for over 35 years. This group included fish with short-lived species, but also a large number of very long-lived species, such as Greenland shark (Somniosus microcephalus). High average maximum life expectancy was also observed in soaring birds. However, aquatic mammals were completely different from the other groups, with over 40% of them being long-lived.

Terrestrial habitats have been dominated mainly by animals that show a clear senescence phenotype. Since the emergence of insects, mammals, and birds occurred at different points of time, senescence must have evolved independently. Consequently, senescence in these groups of animals is likely to be the result of convergent evolution. Thus, we considered the original questions regarding why these three diverse terrestrial clades, show symptoms of senescence and whether senescence could be adaptive. The arguments presented herein suggest that the appearance of senescence in the three major groups of terrestrial animals was a consequence of the evolution of their life histories and as a side effect of the cessation of growth in sexually mature adults. The main mechanisms leading to the loss of this ability for growth were different across clades and occurred at distinct periods of time. The appearance of senescence in various unrelated clades during various periods of animal evolution suggests convergent evolution of senescence, and hence, a lack of homology.

Evidence that the loss of ability of indeterminate growth in terrestrial mammals results in senescence, is provided by secondarily aquatic mammals. In addition to lower rate of senescence, tetrapods that have undergone secondary aquatic adaptation include the longest-living mammals, such as the bowhead whale (Balaena mysticetus), all of which live for over a hundred years. Researchers have examined reproductive materials from mature female bowheads but did not see positive evidence of senescence. Similarly, the maximum and average lifespan of aquatic and semi-aquatic reptiles, which also secondarily returned to the water, exceed those of their terrestrial relatives.

Our analysis suggests that senescence may have emerged as a side effect of the evolution of adaptive features that allowed the colonisation of land. Perhaps specialisation and adaptation of animals to life on land was accompanied by senescent phenotypes, as a side effect of evolution. Thus, senescence in mammals (including humans) may be a trade-off compromise between land colonisation and longevity. In our relatively short synthesis, we presented adaptations that involve animals best suited to life in terrestrial environments. We emphasised that senescence occurred in parallel with highly adaptive traits. Examples of secondary aquatic mammals indicate that it is evolutionarily possible to delay the onset of senescence symptoms. The aquatic environment, which offers conditions that allow animals to grow larger, due to greater density of fluid medium (water) and facilitates the maintenance of appropriate body temperatures, seems to favour negligible senescent phenotypes or an extremely delayed appearance of the signs of senescence, shortly before the death of the individual (as seen in fish, octopus, and whales). Similarly, the functioning of soaring birds seems to be less costly in terms of energy compared to their relatives with passerine-type flights. Hence, we may conclude that an energy-efficient life in a stable environment can delay the symptoms of senescence and promote a longer life.

Considering Mechanistic Links Between Vascular Calcification and Osteoporosis
https://www.fightaging.org/archives/2021/11/considering-mechanistic-links-between-vascular-calcification-and-osteoporosis/

With advancing age, regulatory pathways involved in bone remodeling are activated inappropriately in smooth muscle cells of blood vessel walls and cardiac tissue. The result is calcification of tissue, making it inflexible, and disrupting the normal elasticity. That leads to hypertension and other, worse cardiovascular issues. Inflammatory signaling and the presence of senescent cells appear to be involved in causing this process, but firmly proven chains of cause and effect are yet to be established, as is the case for all too much of the panoply of dysfunctions that arise in the progression of degenerative aging.

Separately, the mechanisms of bone remodeling are disrupted in bone tissue itself, giving rise to an imbalance between deposition on the part of osteoblast cells and resorption on the part of osteoclast cells. The density and resilience of bone decreases over time, leading to osteoporosis. In today's review materials, researchers discuss the regulatory mechanisms involved in both osteoporosis and vascular calcification, noting that while incidence of these conditions are correlated with one another to some degree, it remains unclear as to whether one condition is driving the other, or whether they develop independently from shared root causes, such as the age-related increase in chronic inflammation.

Are vascular calcification and bone loss linked disorders of aging?

A recent review paper elucidates the numerous pathophysiological mechanisms shared by vascular calcification and bone loss, identifying the following key associations. Firstly, vascular calcification is an active process of calcium and phosphate precipitation that involves the transition of the vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Secondly, among the molecules involved in this process, parathyroid hormone (PTH) plays a key role, acting through several mechanisms which include the regulation of the RANK/RANKL/OPG system and the Wnt/ß-catenin pathway, the main pathways for bone resorption and bone formation, respectively. Thirdly, some microRNAs have been implicated as common regulators of bone metabolism, vascular calcification, left ventricle hypertrophy and myocardial fibrosis.

The increase or decrease in tissue and/or serum levels of PTH, the RANK/RANKL/OPG system and the Wnt/bcatenin pathways, calcium, phosphate, FGF23, among the most studied factors, may play a pathogenic role but can also be used as markers of bone and cardiovascular diseases. However, levels of some serum markers should be interpreted with caution, as the correlation between hormone levels and tissue levels needs to be better investigated.

Pathophysiology of Vascular Calcification and Bone Loss: Linked Disorders of Ageing?

This review shows that vascular calcification and bone loss that often coexist in ageing individuals, share numerous pathophysiological mechanisms. In this context, PTH, the RANK/RANKL/OPG system and the Wnt/ß-catenin pathway are the most studied factors. High PTH thus increases bone resorption and bone loss, but also triggers mechanisms that favour vascular calcification involving the RANK/RANKL/OPG and Wnt/ß-catenin pathways. Furthermore, other closely related factors such as calcium, phosphate, FGF23, Klotho, vitamin D and other regulatory factors that regulate PTH render these interactions extremely complex. The presence of low or high PTH levels, and consequently of low or high bone turnover, facilitate the process of deposition of hydroxyapatite in the wall of the vessels, leading to progression of vascular calcification when present for prolonged periods. The process eventually becomes severe, potentially increasing vascular molecular signals in order to reduce "bone deposition in the vessels", which in turn could favour the reduction of normal bone formation. Thus, in the presence of severe vascular calcification, a vicious circle may be established, further reducing bone mass.

The increase or decrease in tissue and/or serum levels of any these factors may play a pathogenic role in both bone loss and vascular calcification, and may be potentially promisingly used as a marker of bone and cardiovascular disease. However, caution should be exerted in the interpretation of these markers. For instance, whereas higher serum levels of sclerostin have been associated with vascular calcification and poor outcomes, this may not necessarily be due to a cause and effect relationship, but to a potential overproduction of sclerostin as a protective factor against vascular calcification. Similarly, serum sclerostin levels have been positively, and not negatively, associated with higher bone mass.

Although the pathogenesis and progression of vascular calcification and bone loss shares several common factors and pathways, it remains a "chicken-and-egg" situation, where it difficult to stablish cause and effect as to whether bone loss is driving vascular calcification or vice-versa, or whether there is a higher level of dysregulation generated by the ageing process that impacts on both tissues simultaneously, using common mechanisms.

Present Calorie Restriction Mimetics are a Poor Substitute for the Practice of Calorie Restriction
https://www.fightaging.org/archives/2021/11/present-calorie-restriction-mimetics-are-a-poor-substitute-for-the-practice-of-calorie-restriction/

The portion of the medical research and development community that is focused on aging spends most of its time and funding on classes of treatment that cannot outperform good lifestyle choices when it comes to improving health and slowing degenerative aging. Why is this? If billions and decades are to be expended on building a pipeline from fundamental research through to clinical trials, why is the goal only an incremental benefit to health, smaller than that produced by regular exercise, intermittent fasting, or the practice of calorie restriction? Why such a lack of ambition, given the many possible projects that could achieve far more?

The small patient advocacy community focused on the treatment of aging as a medical condition spent long years convincing scientific and industry groups that it is both possible and desirable to extend the healthy human life span. The result of that work is, it appears, largely the initiation of projects that simply don't matter in the bigger picture, that won't meaningfully change the shape of later life, that won't greatly extend healthy human life spans.

Today's research materials are a reminder that the lion's share of effort and investment in the longevity industry is devoted to treatments and potential treatments that upregulate cellular stress responses, such as autophagy, to recreate a thin fraction of the natural metabolic outcomes of exercise, fasting, hypoxia, or calorie restriction. It remains the case that far too little attention is given to work that can in principle produce rejuvenation, by repairing the molecular damage that is the underlying cause of aging. Yes, senolytic therapies to clear senescent cells have made the leap, but senolytics see a fraction of the interest given to calorie restriction mimetics.

This is an important topic for continued patient advocacy. It is clearly not enough to convince the institutions of the world to work towards the treatment of aging; that is an important and ongoing battle, but it is only a first step. We must also advocate for a focus on the right sort of research programs, those that are in principle capable of producing sizable gains in health and life span, versus those that are not. If another two decades slip away with nothing to show for it but the clinical approval of varieties of mTOR inhibitor and other calorie restriction mimetic small molecule drugs, then a great opportunity to improve the human condition and save countless lives will have been squandered.

Diet trumps drugs for anti ageing and good metabolic health

A study comparing the impact of diet versus drugs on the inner workings of our cells has found nutrition has a much stronger impact. The pre-clinical study suggests the makeup of our diet could be more powerful than drugs in keeping conditions like diabetes, stroke, and heart disease at bay. Conducted in mice, the research showed nutrition (including overall calories and macronutrient balance) had a greater impact on ageing and metabolic health than three drugs commonly used to treat diabetes and slow down ageing: metformin, resveratrol, and rapamycin.

The research builds on the team's pioneering work in mice and humans demonstrating the protective role of diet and specific combinations of proteins, fats, and carbohydrates against ageing, obesity, heart disease, immune dysfunction, and risk of metabolic diseases, such as type 2 diabetes. Drugs can also target the same biochemical pathways as nutrients. There has been a huge effort to discover drugs aimed at improving metabolic health and ageing without requiring a change in diet. "We discovered dietary composition had a far more powerful effect than drugs, which largely dampened responses to diet rather than reshaped them."

Nutritional reprogramming of mouse liver proteome is dampened by metformin, resveratrol, and rapamycin

Nutrient sensing pathways influence metabolic health and aging, offering the possibility that diet might be used therapeutically, alone or with drugs targeting these pathways. We used the Geometric Framework for Nutrition to study interactive and comparative effects of diet and drugs on the hepatic proteome in mice across 40 dietary treatments differing in macronutrient ratios, energy density, and drug treatment (metformin, rapamycin, resveratrol). There was a strong negative correlation between dietary energy and the spliceosome and a strong positive correlation between dietary protein and mitochondria, generating oxidative stress at high protein intake. Metformin, rapamycin, and resveratrol had lesser effects than and dampened responses to diet. Rapamycin and metformin reduced mitochondrial responses to dietary protein while the effects of carbohydrates and fat were downregulated by resveratrol. Dietary composition has a powerful impact on the hepatic proteome, not just on metabolic pathways but fundamental processes such as mitochondrial function and RNA splicing.

AMPK Activator O304 as an Exercise Mimetic Drug
https://www.fightaging.org/archives/2021/11/ampk-activator-o304-as-an-exercise-mimetic-drug/

Most of the work aimed at treating aging as a medical condition is focused on stress response upregulation, finding ways to trigger some of the regulatory pathways and mechanisms involved in beneficial cellular reactions to the mild stresses of exercise, reduced calorie intake, hypoxia, heat, cold, and so forth. Improved cell behavior leads to improved tissue function, which in turn slows the progression of degenerative aging. Many of these pathways converge on autophagy, and evidence from the study of calorie restriction suggests that improved autophagy is the largest contributing factor.

Autophagy is the name given to a collection of cellular maintenance processes that remove unwanted or damaged structures and proteins, ensuring that they are broken down in a lysosome and the raw materials returned to the cell for reuse. Autophagy becomes less effective with age, and researchers have in recent years identified a range of age-related defects in the various component parts of the autophagic process. Tracing these issues back to root causes is, as for most of the changes observed in cells in aged tissues, quite challenging and very much a work in progress.

Stress response upregulation is much more effective at extending life span in short-lived species than it is in long-lived species. Calorie restriction can increase life span by 40% in mice, but certainly doesn't do that in humans. Stress response upregulation as a strategy for the development of therapies does not seem likely to greatly improve the healthy human life span to a much greater degree than is already possible via lifestyle changes. So it is disappointing that so much of present efforts are directed towards this part of the field. Results in mice should not be taken as indicative of the benefits that these same treatments might achieve in longer-lived species such as our own.

AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice

Metabolic function, cardiac capacity, and vascular flexibility decline progressively with age, which in combination reduce work capacity, mobility, and quality of life. Type 2 diabetes (T2D) and cardiovascular diseases (CVDs) incidence increase with age and are current global epidemics representing major challenges to health care systems. Regular exercise not only increases work/exercise capacity but also counteracts the development of numerous age-related diseases, including several forms of metabolic and CVDs, thus promoting healthy aging. However, aged individuals are frequently unable to engage in regular exercise/physical activity. Thus, there is a large need to develop pharmacological treatments that can increase exercise/work capacity to counteract metabolic dysfunction and improve cardiac and vascular function and thereby promote healthy aging and increase quality of life in the aging population.

Insulin resistance and associated hyperinsulinemia are predictors of age-related diseases such as T2D and CVD. Increased activity of AMP-activated protein kinase (AMPK), a key energy sensor that is activated in response to low energy and glucose levels following exercise, enhances insulin-dependent and insulin-independent skeletal glucose uptake, thus improving glucose homeostasis and insulin resistance. AMPK activity declines however with age. Thus, AMPK has emerged as a potential important link between, and mediator of, numerous positive effects of exercise including protection against age-related diseases.

We previously showed that pan-AMPK activator O304 stimulates AMPK activity and glucose uptake in both skeletal muscle and heart of diet-induced obese (DIO) mice in vivo. In DIO mice, O304 mitigated hyperglycemia, hyperinsulinemia, insulin resistance, and obesity, and in a transgenic type 2 diabetic mouse model, O304 reversed established diabetes. O304 also significantly increased stroke volume, end-diastolic volume, and reduced heart rate in DIO mice, mimicking the cardiac effects of exercise. Thus, AMPK activator O304 efficiently ameliorated obesity-provoked insulin resistance, diabetes, and cardiovascular dysfunction in obese mice. O304 is currently in clinical development, and in a short proof-of-concept phase IIa clinical trial in T2D patients O304 reduced fasting plasma glucose levels and insulin resistance, i.e., HOMA-IR, and increased microvascular perfusion in the calf muscle and reduced blood pressure.

Here we show that the pan-AMPK activator O304, which is well tolerated in humans, prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice. These results provide preclinical evidence that O304 mimics the beneficial effects of exercise. Thus, as an exercise mimetic in clinical development, AMPK activator O304 holds great potential to mitigate metabolic dysfunction, and to improve cardiac function and exercise capacity, and hence quality of life in aged individuals.

Like Elephants, Long-Lived Galapagos Tortoises Exhibit Duplication of Genes Related to Longevity and Cancer Suppression
https://www.fightaging.org/archives/2021/11/like-elephants-long-lived-galapagos-tortoises-exhibit-duplication-of-genes-related-to-longevity-and-cancer-suppression/

Genes determine species longevity, though within a species, and particularly within our species, the estimated involvement of genetic variants in individual life expectancy is becoming ever smaller as ever more data accumulates. Nonetheless, researchers are very interested in the comparative biology of aging, the question of why long-lived species are long-lived in comparison to their closest relatives. Which of the many evolved differences tend to produce a longer life span?

A longer species life span necessarily requires a lower incidence of cancer. Cancer is a numbers game: a larger body size means that there are more cells that can suffer mutation and become cancerous; a longer life allows more time for those cells to suffer mutation and become cancerous. Thus in larger and longer-lived species there must be mechanisms that either (a) lower the rate at which cancerous mutations can occur, or (b) increase the efficiency of cancer suppression mechanisms. These mechanisms are layered, ranging from those inside cells that provoke self-destruction when damage is identified, to the ability of the immune system to detect and destroy cancerous cells.

Elephants are both large and long-lived, and yet have a lower risk of cancer than is the case for our species. In recent years, researchers identified that elephants have many duplicated copies of the TP53 cancer suppression gene. The protein p53 produced from this gene is involved in DNA repair, as well as induction of cellular senescence and programmed cell death in response to DNA damage. It is thus an important part of cellular responses to potentially cancerous mutations. In today's open access paper, researchers report on their discovery of similar duplications in genes related to longevity and cancer suppression in long-lived Galapagos tortoises, indicating that this sort of evolutionary change is probably commonplace in longer-lived species.

It is interesting to consider that continually upregulating TP53 expression in short-lived mammals such as mice does improve cancer suppression, but also shortens life span, via mechanisms that likely include a reduction in stem cell activity and increase in the burden of cellular senescence. Too much vigilance has its costs. Researchers have worked around this issue, in mice at least, via forms of intermittent upregulation that only operate when TP53 is called upon, or via combining p53 upregulation with telomerase upregulation.

Concurrent evolution of anti-aging gene duplications and cellular phenotypes in long-lived turtles

A recurring theme in lifespan and aging regulation is the critical role played by processes that promote cellular protection and maintenance, including the ability of cells to recycle materials, repair damage, and remove waste. Senescent cells, whose numbers greatly increase with age, exhibit declines in these processes, and are also associated with pro-inflammatory phenotypes that are linked to age-related diseases. At the same time, apoptosis, which is the programmed destruction of unfit or damaged cells, is reduced in older individuals. This decline in cell performance in combination with a decreased ability to remove poor-performing cells is central to the aging process. Similarly, cancer can arise from cumulative genotoxic and cytotoxic stress, and apoptosis also plays a primary role in cancer resistance by removing potentially cancerous cells. Thus, if cancer-suppressing mechanisms are similar across species, then larger, longer-lived organisms should be at greater risk of cancer than smaller, shorter-lived ones. While this correlation exists within species, for example, cancer incidence increases with increasing adult height for most cancer types in humans and overall body mass in dogs, there is no such correlation between species - an observation often referred to as "Peto's paradox".

The molecular and cellular mechanisms underlying the evolution of large bodies and long lifespans have been explored in mammals such as elephants, whales, bats, and naked mole rats, but are less well studied in other vertebrates. Reptiles are an excellent system in which to study the evolution of body size and longevity because diverse lineages have repeatedly evolved large body sizes and long lifespans. Turtles, in particular, have lower rates of neoplasia than snakes and lizards, are especially long-lived, and are "slower aging" than other reptiles. Most notably, Galapagos giant tortoises (C. niger) and Aldabra giant tortoises (Aldabrachelys gigantea) can live over 150 years (3-5 times longer than their closest relatives) and weigh over 200 kg (50-100 times heavier than their closest relatives). Galapagos giant tortoises also appear to have evolved a suite of cellular traits that may contribute to their longevity, such as a slower rate of telomere shortening and extended cellular lifespans compared to mammals.

Here, we explore the evolution of body size and lifespan in turtles by integrating several approaches: (1) phylogenetic comparative analysis of body size, lifespan, and intrinsic cancer risk in turtles; (2) gene duplication analysis of aging and cancer-related genes across available turtle genomes; (3) cell-based assays of apoptosis and necrosis in multiple turtle species varying in body size and lifespan. We show that species with remarkably long lifespans, such as Galapagos giant tortoises, also evolved reduced cancer risk. We also confirm that the Galapagos giant and desert tortoise genomes encode numerous duplicated genes with tumor suppressor and anti-aging functions. Our comparative genomic analysis further suggests that cells from large, long-lived species may respond differently to cytotoxic stress, including endoplasmic reticulum (ER) stress and oxidative stress. The combined genomic and cellular results suggest that at least some turtle lineages evolved large bodies and long lifespans, in part, by increasing the copy number of tumor suppressors and other anti-aging genes and undergoing changes in cellular phenotypes associated with cellular stress.

Live Longer World, Podcast Interviews and Newsletter
https://www.fightaging.org/archives/2021/11/live-longer-world-podcast-interviews-and-newsletter/

Live Longer World's Aastha Jain maintains an interesting selection of podcasts and video interviews with various people in and around the longevity industry and the related scientific community focused on interventions in the aging process. That includes an interview with me, from a couple of months ago, should you find yourself interested in a random walk through some of my views on the state of the field.

Live Longer World provides you information on the science and practical mechanisms on how we can slow and reverse aging. For those baffled by me calling aging a disease, the easiest way to think of aging is damage accumulation happening in our bodies. Over time, this damage accumulates, wears us down, leads to onset of diseases, aging, and death. But what if this damage could be reversed? And science is showing that it is indeed possible. We can slow the accumulation of damage and also reverse it, and Live Longer World provides you information on how both are possible through different communication platforms and methods.

The newsletter is focused mostly on science-backed lifestyle methods to slow aging, optimize health, biohack, improve healthspan, and feel more energetic. Simple lifestyle practices can go a long way in maintaining optimal health and a robust immune system. If you care to know best science-backed tools to optimize health, sign up for the newsletter.

The science of aging is moving rapidly and making progress at defeating age-related diseases and aging itself. Live Longer World Podcast takes you right where the action is happening! Through conversations with scientists, entrepreneurs, investors and other advocates revolutionizing the field of longevity science, we tell you how you can be disease-free, reverse aging, and maximize longevity in the future. Further, the YouTube channel covers the video versions of the podcast - discussions with scientists, entrepreneurs, investors and other advocates moving the science and technology of longevity forward.

Dogs Benefit from Time Restricted Feeding
https://www.fightaging.org/archives/2021/11/dogs-benefit-from-time-restricted-feeding/

A common factor in calorie restriction, intermittent fasting, and time-restricted feeding is time spent in a state of hunger. More time spent hungry may be better, up to a point. The signaling associated with hunger upregulates cellular maintenance processes such as autophagy, known to improve health over the long term. While the biochemistry is under ever greater exploration, there is still a lot of work to be accomplished in order to map the dose-response curve for calorie intake versus time spent hungry, as well as how that dose-response curve may differ in different mammalian species. One might look at recent discussions regarding the structure of studies in mice to see that assessments are not as straightforward a matter as might be imagined: mice in studies of calorie restriction are fed once a day. How much of the resulting health benefits are due to this time-restricted feeding versus reduced overall calorie intake?

A variety of diets have been studied for possible anti-aging effects. In particular, studies of isocaloric time-restricted feeding in laboratory rodents have found evidence of beneficial health outcomes. Companion dogs represent a unique opportunity to study diet in a large mammal that shares human environments. The Dog Aging Project has been collecting data on thousands of companion dogs of all different ages, sizes, and breeds since 2019.

We leveraged this diverse cross-sectional dataset to investigate associations between feeding frequency and cognitive function (n = 10,474) as well as nine broad categories of health outcomes (n = 24,238). Controlling for sex, age, breed, and other potential confounders, we found that dogs fed once daily rather than more frequently had lower mean scores on a cognitive dysfunction scale, and lower odds of having gastrointestinal, dental, orthopedic, kidney/urinary, and liver/pancreas disorders. Therefore, our findings suggest that once-a-day feeding in dogs is associated with improved health across multiple body systems.

Notes on the Recent Longevity Week in London
https://www.fightaging.org/archives/2021/11/notes-on-the-recent-longevity-week-in-london/

The yearly Longevity Week events in London are organized by Jim Mellon's network of allies, to promote the longevity industry and the concept of working towards therapies to treat aging as a medical condition. Sadly I could not attend this year, a combination of conflicting events in the US and it being too soon after conferences started up again post-COVID-19 to commit to international travel. Fortunately, one can still find a few notes on the proceedings online, and video of presentations will usually follow.

This week was "Longevity Week" with numerous events organised in the UK on what we now call "geroscience". Geroscience is predicated not only on the idea that human lifespan can be extended well beyond the biblical standard of three score years and ten, but also that we can avoid the degenerative diseases of old age which afflict so many seniors. So "healthspan" - the length of time that we can live without chronic and debilitating conditions such as diabetes, osteoarthritis, rheumatoid arthritis, macular degeneration, Parkinson's, or dementia - is just as important in this discussion as lifespan. That is an important starting point since, although life expectancy has increased significantly across the world within my own lifetime (from about 50 to 70), for many people those additional years are marred by ill health.

This November, a Master Investor event in central London brought together some of the leading scientists and entrepreneurs in this rapidly growing field. "Investing in the Age of Longevity" was the third event of this kind organised by Master Investor, inspired by our chairman Jim Mellon's passionate advocacy for geroscience. Indeed, it all started about five years ago when Jim took a road trip across the USA in a Honda Odyssey with the aim of meeting all the key players - academic scientists, biotech entrepreneurs, and visionary thinkers - who were formulating a body of ideas around the theme of longevity.

There is, as ever, a demographic and economic backdrop to these nascent medical technologies. In terms of the raw demographics, for the first time in the history of humanity there will be more old people (that's over-65s) than youngsters (under-16s) on the planet by 2050 - just 28 years away. The dependency ratio - that's the ratio of the number of people in work and paying tax to the number of people who are retired and receiving pensions - is in free fall in the developed world and is beginning to decline too in developing countries on account of declining fertility rates. These over-65s, to the extent that they get sick, are proving to be an increasing burden on state-funded and insurance-backed healthcare systems. The USA spends just over 17 percent of its GDP on healthcare today; but by 2040, based on current trends, the healthcare burden will double to 34 percent of GDP.

Just as the focus of medical science in the 19th and much of the 20th century was on the need to improve infant mortality and to cure the diseases of childhood, so the primary focus of medical science in the 21st century will be to prevent and cure the diseases of old age. Three leading healthcare economists have calculated that increasing the healthspan of humanity by just one year would be worth 38 trillion a year to the global economy. By increasing healthspans, lifespans will lengthen too.

Exercise Delays T Cell Population Aging
https://www.fightaging.org/archives/2021/11/exercise-delays-t-cell-population-aging/

Exercise delays the aging of the immune system, particularly changes in the distribution of T cell populations, but what are the underlying mechanisms? Researchers here note the existing focus in the scientific community on mitochondrial metabolism in T cells; exercise beneficially affects mitochondrial function, and energy metabolism is an important determinant of T cell behavior. The researchers suggest, however, that the existing evidence is more supportive of effects based on differences in metabolite production and consumption. It is an interesting viewpoint.

The effect of exercise on immune health has been widely studied in various population cohorts, however, exercise-research targeting CD4+ T cells is less represented. Nevertheless, exercise has been shown to modulate both the number and activity of CD4+ T cells, with an increased number of CD4+ T cells observed in the blood of athletes after training. Furthermore, physical fitness can modulate the concentration of immune cell subsets (VO2max exhibiting a large correlation with regulatory T cells (Treg) populations in the blood outside of training). Moreover, exercise can alter the balance of Th17/Tregs (increased Th17 and decreased Treg populations) improving chronic heart failure outcomes in a murine model. In reports that have identified CD4+ T cell subsets, the mechanisms driving these observations are not characterized, however, it is likely that metabolism plays an integral part.

Metabolic programs engaged by T cells directly affect their type and function. Substrate utilization during exercise will vary depending on the exercise type, intensity, and duration. During low to moderate intensity exercise, the main substrates are glucose, glutamine, and fatty acids; with glucose becoming a more prominent fuel source as intensity increases. Considering the importance of mitochondria in cell metabolism, the effects of exercise in mitochondria have been studied extensively. Although it is expected that exercise-related adaptations mainly affect muscle mitochondria, exercise can influence surrounding cells via the availability of metabolites.

In summary, CD4+ T cells include a diverse population with highly varied function. Plasticity is exhibited between CD4+ T cell subsets and linked to numerous maladies such as development and exacerbation of autoimmune disorders and tumorigenesis. Exercise has been shown to effect CD4+ T cells, however, our understanding of the mechanisms surrounding these changes is limited. We propose that exercise could alter CD4+ T cell identity through metabolic responses to exercise, which in turn, affect the availability of metabolites and induce epigenetic remodeling events. To substantiate these claims, more research is needed to profile the epigenetic landscape of CD4+ T cells in response to exercise at the single cell level, identifying intermediate cell subsets, and deciphering the role of exercise on immune cell plasticity.

Heterochronic Parabiosis Reduces Epigenetic Age in Mice
https://www.fightaging.org/archives/2021/11/heterochronic-parabiosis-reduces-epigenetic-age-in-mice/

Heterochronic parabiosis is the surgical linking of the circulatory systems of an old individual and young individual, usually mice. The older mouse shows signs of rejuvenation, while the younger mouse shows signs of accelerated aging. There is a robust ongoing process of debate and discovery regarding the mechanisms by which these effects are mediated. At present it appears that a dilution of harmful factors in old blood is likely to account for most of the outcome, but there is evidence for beneficial factors in young blood to be involved. In the study here, researchers show that epigenetic and transcriptomic measures of age are reduced in old mice following heterochronic parabiosis, and that this effect persists for at least a few months following the end of the intervention.

Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on the biological age of organisms and their long-term health remains unknown. Here, we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the biological age of blood and liver based on epigenetic analyses across several clock models on two independent platforms; remarkably, this rejuvenation effect persisted even after 2 months of detachment.

Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a comprehensive multi-omic rejuvenation effect. In addition, old HPB mice showed transcriptome changes opposite to aging, but akin to several lifespan-extending interventions. Altogether, we reveal that long-term HPB can decrease the biological age of mice, in part through long-lasting epigenetic and transcriptome remodeling, culminating in the extension of lifespan and healthspan.

A Narrow Window for Exercise to Improve Neurogenesis via Growth Hormone in Aged Mice
https://www.fightaging.org/archives/2021/11/a-narrow-window-for-exercise-to-improve-neurogenesis-via-growth-hormone-in-aged-mice/

There is mixed evidence for exercise to improve neurogenesis and cognitive function in very old mice. Researchers here suggest that this is because the duration of an exercise program matters greatly, and there is a comparatively narrow window of time in which the result is a net gain in function. This may be an example of the frailty of old age: mild stresses such as exercise that are robustly beneficial in younger individuals become more of a balancing act between cost and benefit in age-damaged individuals. The results are interesting, and will likely guide further explorations of the effects of exercise in very old human patients. That said, it isn't clear that the findings are in any way informative as to the dose-response curve for the effects of exercise on neurogenesis and cognitive function in old humans.

Hippocampal function is critical for spatial and contextual learning, and its decline with age contributes to cognitive impairment. Exercise can improve hippocampal function, however, the amount of exercise and mechanisms mediating improvement remain largely unknown. Here, we show exercise reverses learning deficits in aged (24 months) female mice but only when it occurs for a specific duration, 5 weeks, with longer or shorter periods proving ineffective.

While others have reported that a 5-week period of daily voluntary exercise results in the improvement of hippocampal cognitive function in aged mice, surprisingly, our results reveal that if we extended this period of exercise, there was abrogation of cognitive improvement. The discovery of a "sweet spot" of exercise duration critical for both neurogenic activation and improved spatial learning may help explain previous conflicting reports of the efficacy of exercise in improving cognitive improvement in aged mice.

A spike in the levels of growth hormone (GH) and a corresponding increase in neurogenesis during this sweet spot mediate this effect because blocking GH receptor with a competitive antagonist or depleting newborn neurons abrogates the exercise-induced cognitive improvement. Moreover, raising GH levels with GH-releasing hormone agonist improved cognition in nonrunners. We show that GH stimulates neural precursors directly, indicating the link between raised GH and neurogenesis is the basis for the substantially improved learning in aged animals.

Modulation of the Aged Gut Microbiome to Benefit Health is a Field in its Infancy
https://www.fightaging.org/archives/2021/11/modulation-of-the-aged-gut-microbiome-to-benefit-health-is-a-field-in-its-infancy/

Research of the past decade makes it clear that it is plausible and possible to alter the aged gut microbiome in ways that will reduce chronic inflammation and improve long-term health. This goal has been achieved in animal models via a range of different means, including flagellin immunization and fecal microbiota transplantation. In short-lived species, healthy life spans can be extended by restoring a more youthful gut microbiome, and in our own species, the detrimental changes that take place in gut microbiome populations are increasingly well catalogued. The next step has yet to be taken in earnest, however: to roll out human trials of the known ways to beneficially alter the gut microbiome.

Changes in the intestinal microflora with aging are related to the pathogenesis of age-related chronic diseases. Dietary intervention, exercise, and drug therapy are currently the most studied anti-aging measures and can improve the intestinal microbial imbalance caused by aging and promote a healthier intestinal environment to achieve anti-aging effects. In addition, gut microbiota modification represents a promising intervention for anti-aging and aging-related diseases, such as the use of probiotics, prebiotics, and synbiotics.

Studies suggest that modifying the gut microbiota of the elderly population by the intake of functional food as probiotics, prebiotics, or synbiotics may be an effective strategy to counteract natural aging. At the same time, these functional products may be suitable, affordable, and economical to most elderly people. However, their effects on health are complex, depending on individual populations and the duration of treatments. Evidence of probiotic, prebiotic and synbiotic use in elderly people is in its infancy compared with other measures.

Despite much research on these interventions, there are no firm conclusions about the benefits for human health. The reasons may be as follows: (1) Most of the relevant studies have been conducted in laboratory and animal models. These findings do not necessarily apply to humans directly. (2) Most clinical trials with humans are short-term and insufficient to understand long-term health effects. (3) Humans are quite different from each other in terms of sex, size, age, genetics, environment, lifestyle, and other factors. An anti-aging intervention that was found to help one person might not have the same effect on another. (4) Although many probiotics have proven strong safety profiles, we should still be careful to monitor their potential risks in different populations in the development of new probiotics.

Therefore, future research needs to focus on addressing these issues to better understand the safety and efficacy of these anti-aging measures in humans. In addition, although much hope and investment are currently focused on drug development, the application of anti-aging drugs in humans still has a long way to go. It is important to note that sensible habits may be more effective at extending healthspan than taking a medication. This means eating healthy foods, exercising, drinking alcohol in moderation or not at all, not smoking, getting adequate sleep, and maintaining an active lifestyle.

In Type 2 Diabetes, Arterial Stiffening Causes Increased Structural Damage to the Brain
https://www.fightaging.org/archives/2021/11/in-type-2-diabetes-arterial-stiffening-causes-increased-structural-damage-to-the-brain/

Researchers here mine patient data in order to demonstrate that type 2 diabetes combines with the age-related stiffening of blood vessels to produce greater structural damage in the brain, leading to a more rapid cognitive decline. This correlation between stiffening and damage was not observed in non-diabetic patients. This is an interesting result, as a reasonable view of the consequence of blood vessel stiffening with age is that it will produce increased blood pressure and consequence pressure damage to delicate tissues regardless of other factors. The authors conclude that the most likely explanation is that diabetes makes this process significantly worse, and thus more easily identified in patient data.

Cerebrovascular dysfunction has been proposed as a possible mechanism that underlies cognitive impairment in the context of type 2 diabetes mellitus (DM). Although magnetic resonance imaging (MRI) evidence of cerebrovascular disease, such as white matter hyperintensities (WMH), is often observed in DM, the vascular dynamics underlying this pathology remain unclear. Thus, we assessed the independent and combined effects of DM status and different vascular hemodynamic measures (i.e., systolic, diastolic, and mean arterial blood pressure and pulse pressure index [PPi]) on WMH burden in cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI).

559 older adults (mean age: 72.4 years) from the Alzheimer's Disease Neuroimaging Initiative were categorized into those with diabetes (DM+; CU = 43, MCI = 34) or without diabetes (DM-; CU = 279; MCI = 203). Participants underwent BP assessment, from which all vascular hemodynamic measures were derived. The presence of DM, but not PPi values, was independently associated with greater WMH burden overall after adjusting for covariates. Higher PPi values predicted greater WMH burden in the DM group only. No significant interactions were observed in the CU group.

Results indicate that higher PPi values are positively associated with WMH burden in diabetic older adults with MCI, but not their non-diabetic or CU counterparts. Our findings suggest that arterial stiffening and reduced vascular compliance may have a role in development of cerebrovascular pathology within the context of DM in individuals at risk for future cognitive decline. Given the specificity of these findings to MCI, future exploration of the sensitivity of earlier brain markers of vascular insufficiency (i.e., prior to macrostructural white matter changes) to the effects of DM and arterial stiffness/reduced vascular compliance in CU individuals is warranted.

Evidence that Metformin Does Not Interfere in the Beneficial Response to Exercise
https://www.fightaging.org/archives/2021/11/evidence-that-metformin-does-not-interfere-in-the-beneficial-response-to-exercise/

There have been suggested that metformin, a at best weak calorie restriction mimetic, can suppress some of the beneficial metabolic response to exercise. Metformin is in general a poor choice in comparison to mTOR inhibitors when it comes to animal evidence for an ability to modestly slow the progression of aging. The primary human evidence for metformin to be useful, and why it attracted interest in the first place, comes from a large study of diabetic patients, and the gain in life expectancy was not large. Researchers here provide evidence against any suppression by metformin of beneficial mechanisms resulting from exercise, but I can't say that this does much to make metformin an attractive option. At the end of the day, small effect sizes are just not worth chasing, given the many other lines of research and development that offer greater promise.

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise with or without metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed.

Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress, and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g. the gut.

Macrophages Essential to Limb Regeneration in the Axolotl Emerge from the Liver
https://www.fightaging.org/archives/2021/11/macrophages-essential-to-limb-regeneration-in-the-axolotl-emerge-from-the-liver/

Regeneration from injury is an intricate dance between stem cells, somatic cells, senescent cells, and immune cells. In particular, research into the biochemistry of species such the axolotl that can regenerate limbs and organs has identified the innate immune cells known as macrophages as essential to the process. Specific differences in macrophage behavior between more regenerative species such as the axolotl and less regenerative species such as our own are still under exploration. Here, researchers uncover a greater level of complexity in axolotl regeneration, in that only some macrophages are important to scar-free regeneration, and these cells originate in the liver rather than the bone marrow.

In 2013 it was discovered that a type of white blood cell called a macrophage is essential to limb regeneration in the axolotl. Without macrophages, which are part of the immune system, regeneration did not take place. Instead of regenerating a limb, the axolotl formed a scar at the site of the injury, which acted as a barrier to regeneration, just as it would in a mammal such as a mouse or human. Now, in a new study, researchers have identified the origin of pro-regenerative macrophages in the axolotl as the liver. By providing science with a place to look for pro-regenerative macrophages in humans - the liver, rather than the bone marrow, which is the source of most human macrophages - the finding paves the way for regenerative medicine therapies in humans.

Although the prospect of regrowing a human limb may be unrealistic in the short term due to its complexity, regenerative medicine therapies could potentially be employed in the shorter term in the treatment of the many diseases in which scarring plays a pathological role, including heart, lung and kidney disease. "If axolotls can regenerate by having a single cell type as their guardian, then maybe we can achieve scar-free healing in humans by populating our bodies with an equivalent guardian cell type, which would open up the opportunity for regeneration."

Although it remains to be seen if achieving scar-free healing in mammals will allow regeneration to proceed, researchers believe that may be the case. Because mammals already possess the machinery for regeneration - young mice can regenerate, as can human newborns - mammalian regeneration may simply be a matter of removing the barrier posed by scarring. "In axolotls, macrophages act as a brake on fibrosis, or scarring. Humans may possess macrophages that are doing their hardest to repair the damage, but are being held back. If we can engineer human macrophages to promote scar-free healing, we might be able to achieve a huge improvement in repair with just a little tweak. We have the luxury in the salamander of being able to work out which macrophage functions are essential to scar suppression and regeneration, gene by gene if we have to. If we can find out what that is, then maybe we can get that interaction happening in mammals."