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/

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Contents

• Matching Funds Now Triple Year End Donations to Fund Rejuvenation Research at the SENS Research Foundation
• A Tour of Longevity Industry Therapies Presently in Clinical Trials
• Towards Control Over the Dynamic Equilibrium of Bone Tissue Maintenance
• In Vivo Reprogramming Reverses Vision Loss and Damage in a Mouse Model of Glaucoma
• Mechanisms by which Calorie Restriction Delays the Onset of Sarcopenia
• Low Dose PPARγ Agonist Treatment Started in Mid-Life Extends Median Lifespan by 11% in Mice
• Older Obese Patients Can Lose Weight Just as Readily as Younger Obese Patients
• Immune System Aging as Only Loosely Coupled to the Rest of Aging
• Using Inflammatory Signaling to Lure Transplanted Stem Cells to Damaged Locations in the Body
• Sestrin Mediates Some of the Benefits of Calorie Restriction in Flies
• Senescent Cells and Changes in Systemic Factors in Aging
• Adipogenic Lineage Precursor Cells Upregulate Osteoclast Function via RANKL, Contributing to Bone Loss with Age
• Longevity Industry 1.0, the Book
• The Distinct Mechanisms of Aging Interact with One Another
• PDK1 Inhibition Reverses Cellular Senescence

Matching Funds Now Triple Year End Donations to Fund Rejuvenation Research at the SENS Research Foundation
https://www.fightaging.org/archives/2020/11/matching-funds-now-triple-year-end-donations-to-fund-rejuvenation-research-at-the-sens-research-foundation/

The SENS Research Foundation is one of the most important of the scientific and advocacy institutions presently working to make sure that viable approaches to rejuvenation advance to the point at which they can be commercially developed for use in human medicine. If you are deciding on where to make a charitable contribution for the end of 2020, then look no further than this organization, currently running their year end fundraiser. The next 300,000 of donations are presently tripled by matching funds provided by supporters - so jump in while that is the case!

SENS Research Foundation 2020 End of Year Fundraiser

Thanks to a generous matching challenge by Oculus co-founder Michael Antonov, up to 600,000 donated before the end of 2020 will be doubled! But wait, there's more. A team of SRF supporters - Brendan Iribe, Karl Pfleger, Jim Mellon, Dave Fisher, Christophe Cornuejols and Larry Levinson - have joined forces to offer a further 300,000 matching grant. This pool of funds runs in parallel to Michael's challenge, which means the next 300,000 donated will be tripled!

The SENS Research Foundation has long specialized in unblocking areas of research relevant to aging that have received too little attention and funding. Notable successes include the discovery of bacterial enzymes to degrade persistent molecular waste such as A2E, a cause of retinal degeneration, as well as the creation of cyclodextrin molecules that can sequester 7-ketocholesterol, a toxic metabolic byproduct that contributes to numerous age-related and other conditions. The former program led to preclinical development at LysoClear, a part of the Ichor Therapeutics portfolio, and the latter gave rise to the spin out company Underdog Pharmaceuticals. Further, the SENS Research Foundation funded work on the tools needed to work with glucosepane, an advanced glycation endproduct that forms the majority of persistent cross-links in aged human tissue, and that led to Revel Pharmaceuticals, a company funded to develop candidate cross-link breakers.

There are other examples and other projects still underway on mechanisms necessary to produce human rejuvenation. The SENS Research Foundation gets things done, and funds provided go a long way towards ensuring that our personal futures are long and healthy. The only way to get there is to build better medicine, and that starts with the sort of work carried out at the SENS Research Foundation, supported by everyday philanthropists and people of vision, just like you and I.

A Tour of Longevity Industry Therapies Presently in Clinical Trials
https://www.fightaging.org/archives/2020/12/a-tour-of-longevity-industry-therapies-presently-in-clinical-trials/

The longevity industry is presently still quite young, a hundred and something companies that are largely still at the preclinical stage of development, most founded in the last couple of years. Even if we want to be broadly generous as to which companies and projects are to be included in our definition of the industry, no newly developed therapies to treat the mechanisms of aging have yet been approved by the FDA, although a few have made it to phase 3 clinical trials. This is just a matter of time, however; it can take a decade of hard work to go from an idea to an approved therapy, and very few longevity industry companies are even half that age.

Of perhaps more immediate interest are existing approved drugs that appear to have a meaningful effect on mechanisms of aging. The most important of these are widely used chemotherapeutics that have been found to selectively kill senescent cells, and thereby produce rejuvenation in mice. No-one noticed this potential for intervention in the aging process while such drugs were being developed in animal models of cancer and used in cancer patients, for all the obvious reasons. The dosing was quite different, the lifespans of the animals and patients largely quite short, and the disruptions of cancer and high dose chemotherapy masked the benefits that can be obtained via a different approach to usage.

Back to the new therapies under development and the rapidly growing longevity industry, there is more than enough work taking place at present for a community of speculators and spectators to emerge, of various degrees of organization, professionalism, and commercial inclinations. I'll point out one of the more market-focused examples today, with a couple of posts that tour the handful of longevity industry clinical trials underway or recently conducted. Not all are targeting aging, such as the work of Gensight on allotopic expression of mitochondrial genes to treat inherited mitochondrial disease, and these are only relevant because they exercise approaches that can later be turned to address aging.

#015: A Review of Every Single Longevity Therapy in Clinical Trial Today. (PART 1)

Currently there are 28+ anti-aging therapies in human clinical trials spanning a variety of strategies, targets, indications, companies, and modalities. The trials are conducted by companies - private and public - but also universities and non-profit groups. There are also perhaps 100 more pre-clinical companies working on aging in addition to this effort. If any one of the therapies in the first volley on the problem of aging achieve success - even if modest - it could trigger investor hype rivaling the biggest bubbles in history. The zero to one moment in human life extension will change everything.

With the exception of maybe Nir Barzilai's TAME metformin trial (not yet registered), none of the anti-aging therapies currently being tried directly use aging as their clinical endpoint. Most trials instead measure a therapy's efficacy with respect to a specific age-related disease rather than aging itself. Or sometimes the indication is a disease that can be treated with a tool developed from an aging perspective. This is because: (1) The FDA does not recognize aging as an indication (yet). (2) It is expensive to run trials that measure lifespan in humans. (3) We don't have have robust surrogate biomarkers for aging (yet). (4) It is easier to demonstrate clinical significance in an age-related disease than aging itself.

#016: Every Single Longevity Therapy in Clinical Trial Today (PART 2)

Aging is a malleable biological process. Scientists have been precisely turning the knobs of aging in model organisms since the 1990s. Presently we have reached an inflection point: Therapies developed in the context of longevity science are being tested in human patients today.

LYG-LIV0001 - LyGenesis

Perhaps one of the more ambitious clinical trials. LyGenesis is a Juvenescence-backed startup spun out of research at the University of Pittsburgh. The company is attempting to regrow livers by injecting allogenic liver cells into patient lymph nodes. The lymph nodes act as bioreactors and slowly regrow into functional livers - at least in the pre-clinical experiments done on pigs. Their Phase 2 trial includes patients with end-stage liver disease. If successful the company plans to also use the same strategy to regrow the thymus (reversing immunosenescence) and also pancreatic islet cells (reversing diabetes).

SkQ1 - Mitotech

Mitotech is an anti-aging company that develops therapies that protect the mitochondria from reactive oxygen species (ROS). SkQ1 is an anti-oxidant that can easily penetrate the mitochondrial membrane where it can inhibit ROS. In particular, SkQ1 protects cardiolipin, an important protein found in the inner mitochondrial membrane. Dry eye might not sound like a very sexy anti-aging therapy. But this trial is just one small step in the journey of treating mitochondrial diseases, many of which are age-related.

Nicotinamide riboside - ChromaDex

NAD+ levels decrease with age so the hypothesis is that boosting NAD+ levels can have potential anti-aging benefits. There are several chemical precursors to NAD+ but the two most popular are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). ChromaDex is the patent holder of NR and sponsors a number of clinical trials to support the case for its potential anti-aging properties. This time they are measuring hospitalization duration for patients with tissue damage. Given the small size of the study (84 participants) and probable heterogeneity in the illnesses, I have a hard time seeing how anything definitive will be elucidated. This is just one trial of many exploring the benefits of NAD+ precursors / booster. These NAD+ precursor compounds are generally considered safe so I'm excited to see what can benefits can be demonstrated in trials.

Towards Control Over the Dynamic Equilibrium of Bone Tissue Maintenance
https://www.fightaging.org/archives/2020/12/towards-control-over-the-dynamic-equilibrium-of-bone-tissue-maintenance/

Bone loses mass and strength with age, leading to the condition called osteoporosis. The extracellular matrix of bone is dynamically remodeled throughout life, built up osteoblast cells and broken down by osteoclast cells. Osteoporosis is the result of a growing imbalance in cell activity and cell creation that favors osteoclasts. There are many contributing causes, and some uncertainty of which of these causes are more or less important. The chronic inflammation that accompanies aging does appear to be important, particularly that connected to the senescence-associated secretory phenotype (SASP) of senescent cells.

Given that osteoporosis is an imbalance, there are many potential ways to treat the condition, only some of which address the root causes. Any methodology that enhances osteoblast activity to a suitable degree or suppresses osteoclast activity to a suitable degree should be compensatory and beneficial, all other things remaining equal. That said, one would expect targeting the root causes of the imbalance to be a better approach, more likely to produce a larger effect size, and likely to have other beneficial effects elsewhere in the body. For example, the use of senolytic drugs to remove senescent cells is beneficial in many ways beyond the plausibly beneficial impact of a reduced SASP on processes of bone maintenance.

Current advances in regulation of bone homeostasis

Bone homeostasis in the adult skeleton is complex processes. Human skeletal tissue is a constant state of remodelling. The three main bone cells involve in this remodelling process - osteoblasts, osteoclasts and osteocytes via regulation of molecular signalling pathways. In bone remodelling, the discrete zones of bone are resorbed by osteoclasts and substituted by fresh bone by osteoblasts, allowing for repair of bone micro-injury and adapting of bone niche for control of mechanical strengths.

Osteoblast cells are energetic in protein synthesis and matrix secretion to preserve and form new healthy bones. Following mineralization of bone matrix, fully differentiated and matured osteoblasts become osteocytes and are implanted in the bone matrix. During bone remodelling process, mechanosensory cells, osteocytes act as bone orchestrators. This remodelling process is regulated by several local (e.g., growth factors, cytokines, chemokines) and systemic (e.g., estrogens) factors that all together subscribe for bone homeostasis.

In bone modelling process, i.e., during bone development and bone resorption stages, osteocytes act autonomously to fine-tune bone structure. Interestingly, in bone remodelling process, these cells act recycler to restore and keep skeletal health. After osteoclast-mediated bone resorption sequence, the eroded surface of trabecular bone is engaged by osteoblasts that make bone matrix and then undertake mineralization. Under normal physiological conditions of bone homeostasis, osteoclastic action is closely associated with osteoblastic action in such a way that the eroded bone is completely exchanged by fresh bone. Definitively, fluctuating this homeostatic equilibrium in favour of excessive osteoclast activity turns to bone pathological conditions such as osteoporosis, Paget's disease, rheumatoid arthritis (RA), osteoarthritis, and autoimmune arthritis.

Osteoporosis can be prevented and improved musculoskeletal health by using numerous pharmacotherapies such as biphosphonates; selective estrogen receptor modulators (SERMs); hormone therapies; strontium ranelate; denosumab (a human monoclonal antibody with specificity for RANKL); romosozumab (a monoclonal antibody that binds to and inhibits sclerostin) or stimulating bone formation called anabolic medications e.g., PTH preparations and calcitonin therapy have been verified the effects of increased bone mineral density and decreased risk of skeletal fractures.

However, these treatments have some side effects, such as oily skin, fluid retention, nausea, long-term toxicity, and even prostate cancer in males and thus natural therapies that incur better therapeutic activities and fewer side effects are hunted. Therefore, searching for small molecules that precisely suppress osteoclastic action is a favourable approach of the drug discovery for the treatment and management of bone-related diseases including osteoporosis.

In Vivo Reprogramming Reverses Vision Loss and Damage in a Mouse Model of Glaucoma
https://www.fightaging.org/archives/2020/12/in-vivo-reprogramming-reverses-vision-loss-and-damage-in-a-mouse-model-of-glaucoma/

Several research groups and companies are working on in vivo applications of cellular reprogramming. Today's research materials cover recent work from David Sinclair's team showing off the use of reprogramming to produce regeneration of damaged nervous system tissue in the eye and optic nerve. Glaucoma is a condition in which rising pressure in the eyeball progressively harms the retina and optic nerve. Since nerve tissue doesn't regenerate well in mammals, loss of vision is irreversible. This is one of many conditions for which the ability to regenerate nerve tissue would be a great benefit.

Since its discovery, reprogramming has been used to produce induced pluripotent stem cells from any other type of cell. That process has been found to reverse age-related changes in epigenetic patterns and mitochondrial function characteristic of cells in old tissues. Introducing the factors capable of reprogramming cells into a living animal may produce effects akin to stem cell therapy by converting a small number of cells into induced pluripotent stem cells, followed by stem cell signaling that beneficially affects tissue health more broadly. Alternatively, many cells may have their epigenetic markers reset to a more youthful state without losing their identity to become induced pluripotent stem cells. Or both. Beyond this, there is certainly the threat of cancer or structural damage to tissue through the conversion of too many cells, and this class of therapy will require careful development to ensure safety, even as the mouse data continues to look quite interesting.

David Sinclair has been pushing an epigenetic-centric view of aging of late, with analogies to information systems and computing. The most interesting part of the the supporting work suggests that DNA repair of double strand breaks has the side-effect of driving alteration of the epigenome in characteristic ways with age. That will be an important connection between stochastic nuclear DNA damage and deterministic global effects throughout the body, should the evidence continue to hold up.

As this illustrates, however, epigenetic change is a downstream issue in aging, a reaction to events and a changing environment, not a first cause. Fixing it may or may not turn out to be particularly useful in the broader picture of aging, depending on exactly where it sits in the web of cause and consequence. As a comparable example, hypertension is a major downstream issue in aging. It is far removed from root causes such as cross-link formation and inflammation, but is also a proximate cause of many forms of further dysfunction, such as pressure damage to delicate tissues in the brain. Controlling hypertension without addressing its causes is both possible and beneficial - but the benefits are limited by the fact that those root causes are still there, chewing away at the body in a thousand other ways.

Scientists reverse age-related vision loss, glaucoma damage in mice

Scientists have successfully restored vision in mice by turning back the clock on aged eye cells in the retina to recapture youthful gene function. The team used an adeno-associated virus (AAV) as a vehicle to deliver into the retinas of mice three youth-restoring genes - Oct4, Sox2, and Klf4 - that are normally switched on during embryonic development. The three genes, together with a fourth one, which was not used in this work, are collectively known as Yamanaka factors. The treatment had multiple beneficial effects on the eye. First, it promoted nerve regeneration following optic-nerve injury in mice with damaged optic nerves. Second, it reversed vision loss in animals with a condition mimicking human glaucoma. And third, it reversed vision loss in aging animals without glaucoma.

The team's approach is based on a new theory about why we age. Most cells in the body contain the same DNA molecules but have widely diverse functions. To achieve this degree of specialization, these cells must read only genes specific to their type. This regulatory function is the purview of the epigenome, a system of turning genes on and off in specific patterns without altering the basic underlying DNA sequence of the gene.

This theory postulates that changes to the epigenome over time cause cells to read the wrong genes and malfunction - giving rise to diseases of aging. One of the most important changes to the epigenome is DNA methylation, a process by which methyl groups are tacked onto DNA. Patterns of DNA methylation are laid down during embryonic development to produce the various cell types. Over time, youthful patterns of DNA methylation are lost, and genes inside cells that should be switched on get turned off and vice versa, resulting in impaired cellular function. Some of these DNA methylation changes are predictable and have been used to determine the biologic age of a cell or tissue. Yet, whether DNA methylation drives age-related changes inside cells has remained unclear. In the current study, the researchers hypothesized that if DNA methylation does, indeed, control aging, then erasing some of its footprints might reverse the age of cells inside living organisms and restore them to their earlier, more youthful state.

Reprogramming to recover youthful epigenetic information and restore vision

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity. Changes to DNA methylation patterns over time form the basis of ageing clocks, but whether older individuals retain the information needed to restore these patterns - and, if so, whether this could improve tissue function - is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4, Sox2, and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information - encoded in part by DNA methylation - that can be accessed to improve tissue function and promote regeneration in vivo.

Mechanisms by which Calorie Restriction Delays the Onset of Sarcopenia
https://www.fightaging.org/archives/2020/12/mechanisms-by-which-calorie-restriction-delays-the-onset-of-sarcopenia/

The practice of calorie restriction is well documented to slow the progression of aging in mammals. In humans, there is comprehensive evidence for it to improve measures of health and reduce the risk of age-related disease. The mechanisms by which calorie restriction produces benefits are essentially the same across species, an upregulation of various stress response mechanisms that maintain and repair cell function. The short-term health benefits, the specific outcomes resulting from this favorable alteration in the operation of cellular metabolism, are also very similar. However, the extension of life span produced by calorie restriction diminishes as species life span increases. Calorie restriction can extend life in mice by up to 40%, but is thought to only add a few years to human life span.

Nonetheless, improved health is improved health, and calorie restriction does more for long-term health in humans than near any other available intervention. Perhaps only senolytic drugs that clear lingering senescent cells from old tissues will improve upon the benefits for older people, but a head to head comparison has yet to take place.

Today's open access paper offers a narrow focus on the interaction between calorie restriction and one specific age-related condition. It is a review of what is known of the mechanisms by which calorie restriction slows the onset of sarcopenia, the widespread loss of muscle mass and strength that takes place with advancing age. There are many contributing causes of sarcopenia, all of which interact with one another, though the most important are likely (a) a decline in muscle stem cell activity, leading to a reduced supply of new muscle cells to maintain this tissue, (b) damage and loss of function in neuromuscular junctions that link the nervous system to muscles.

Caloric restriction: implications for sarcopenia and potential mechanisms

Epidemiological investigations have indicated that the muscle mass of the human body decreases by approximately 1.5% yearly after the age of 50 and by 2.5-3.0% yearly after the age of 60. The incidence rate of sarcopenia among individuals over 80 years old is as high as 50%. Studies have shown that a 10% decrease in muscle mass leads to a decrease in immune function and an increase in the risk of infection. A 20% reduction in muscle mass results in muscle weakness, a decreased ability to participate in activities of daily living, and an increased risk of falling. A 30% reduction in muscle mass results in disability, loss of independent living ability, and failure of wound and pressure ulcer healing. A 40% reduction in muscle mass results in a markedly increased risk of death from pneumonia, respiratory dysfunction, etc.

The main manifestations of sarcopenia in elderly individuals are a decreased cross-sectional area of muscle fibers and reduced muscle strength and function. Clinical studies have shown that the reduction in muscle mass is much greater in the lower limbs than in the upper limbs. Gait speed or the short physical performance battery (SPPB) are commonly used to assess muscle function. Muscle strength tends to decrease with age, as manifested by reduced grip strength and knee joint extension, weakened hip joint bending activity, decreased pace, and increased time to maximal muscle contraction compared with those of young individuals. Additionally, the number and the proliferation and differentiation abilities of muscle stem cells (MuSCs), which play an important role in muscle cell regeneration, are reduced. The number of MuSCs in aged mice is 50% lower than that in young mice.

A recent study found that CR can improve the function of adult stem cells, including the regeneration ability of skeletal MuSCs. To study whether CR can affect the rhythmic activity of stem cells during aging, researchers conducted a 25-week comparative observation of aged mice that consumed a control diet or a diet with 30% fewer calories than the control diet. In this study, except for the reduction in body weight, the aging characteristics related to epidermal and muscle tissue in mice were significantly ameliorated in the CR group compared with the control group. Additional studies have indicated that not stem cells themselves but the stem cell microenvironment is the key factor mediating stem cell activation, proliferation and differentiation.

Mitochondrial dysfunction is an important factor leading to age-related muscular atrophy. Considering the dependence of skeletal muscle on ATP, loss of mitochondrial function, which can lead to a decrease in strength and endurance, is especially obvious in skeletal muscle. CR can preserve the integrity and function of mitochondrial structure via reducing oxidative damage. Previous studies have shown that CR reduces proton leakage and ROS generation in mitochondria in skeletal muscle while enhancing the expression of ROS scavenging-related genes. In addition, CR may alter the fatty acid composition of the mitochondrial membrane, reduce lipid oxidation, and reduce proton leakage.

Accumulating evidence suggests that apoptosis may constitute a fundamental mechanism driving the onset and progression of sarcopenia. There are two main pathways of apoptosis: activation of the apoptotic enzyme caspase through extracellular signaling and activation of caspases through the release of mitochondrial apoptosis activators. These activated caspases can degrade important proteins in cells and induce apoptosis. The gene expression and cleavage of pre-caspase-3 in the gastrocnemius muscle were significantly reduced in CR mice compared with control mice. In addition, CR increased the content of apoptosis inhibitors in the cytoplasm.

Experimental data strongly suggest that mTOR activity increases during aging, beginning in middle age and resulting in progressively altered mitochondria, in turn leading to mitochondrial oxidative stress and thus the induction of catabolic processes, including protein degradation, apoptosis, and necrosis. This elevated catabolic activity results in muscle fiber loss, atrophy, and damage. Recent evidence has shown that CR downregulates mTORC1 signaling in skeletal muscle independent of dietary protein intake. Moreover, a paper published in 2019 indicated that the effects of CR on mTOR signaling in skeletal muscles are age-dependent. CR altered mTOR signaling in the soleus muscles in middle-aged rats but not in young and adult rats.

Autophagy is essential for overall cellular health because in some residual tissues, the lack of an autophagic response gradually results in the accumulation of damage within the cells, eventually leading to cell death and loss of tissue function. In vivo studies have demonstrated that CR can increase autophagic responses in skeletal muscle. Additional studies have shown that CR regulates the transcription factor Forkhead box O3 (FOXO3), which is associated with human longevity, and recent studies have shown that muscle atrophy is associated with the expression of the transcription factor FOXO3 and other downstream target skeletal muscle atrophy-related proteins.

In summary, the protective effects of CR on sarcopenia are manifested as improved protein quality, maintenance of muscle strength, and enhanced muscle function, and these effects may be achieved via mitigation of cellular oxidative stress, promotion of mitochondrial function, alleviation of the inflammatory response, inhibition of apoptosis, activation of autophagy, and other mechanisms.

Low Dose PPARγ Agonist Treatment Started in Mid-Life Extends Median Lifespan by 11% in Mice
https://www.fightaging.org/archives/2020/11/low-dose-ppar%ce%b3-agonist-treatment-started-in-mid-life-extends-median-lifespan-by-11-in-mice/

Researchers here note a modest life extension in mice resulting from long-term treatment with low doses of a PPARγ agonist drug, started in mid-life. This is thought to be an adjustment that acts to suppress inflammation and improve insulin metabolism, both strongly connected to the way in which cellular metabolism determines pace of aging. The size of the effect in mice is small enough to think that it would have little effect on life span in our species, however. Effects derived from this sort of metabolic adjustment have a much larger impact on life span in short-lived species than they do in long-lived species, as most of the relevant stress response mechanisms connecting metabolism to environmentally induced variations in the pace of aging evolved as a part of the life-extending response to calorie restriction. A seasonal famine is a long time to a mouse, not so long to a human, so only the mouse evolves a sizable gain in life span when these stress response mechanisms are trigger.

Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia.

Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with an 11% median lifespan extension.

A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.

Older Obese Patients Can Lose Weight Just as Readily as Younger Obese Patients
https://www.fightaging.org/archives/2020/11/older-obese-patients-can-lose-weight-just-as-readily-as-younger-obese-patients/

It is the common wisdom that fat tissue becomes harder to lose with age, that metabolism tilts in the direction of wanting to retain that fat. The results of this study are a counterpoint, suggesting that, given the same adherence to the usual weight loss protocol of eating fewer calories, older people can in fact lose weight just as readily as younger people. Visceral fat tissue is harmful to long-term health in numerous ways, but particularly through the generation of chronic inflammation that accelerates the onset and progression of all of the common fatal age-related conditions. The only thing worse than gaining excess fat tissue is holding on to it over time, and letting the damage and dysfunction to your tissues accumulate as a result.

Obese patients over the age of 60 can lose an equivalent amount of weight as younger people using only lifestyle changes, according to a new study that demonstrates that age is no barrier to losing weight. The researchers hope that their findings will help to correct prevailing societal misconceptions about the effectiveness of weight loss programmes in older people, as well dispel myths about the potential benefits of older people trying to reduce their weight.

For this retrospective study, researchers randomly selected 242 patients who attended an obesity service between 2005 and 2016, and compared two groups (those aged under 60 years and those aged between 60 and 78 years) for the weight loss that they achieved during their time within the service. All patients had their body weight measured both before and after lifestyle interventions administered and coordinated within the obesity service, and the percentage reduction in body weight calculated across both groups.

When compared, the two groups were equivalent statistically, with those aged 60 years and over on average reducing their body weight by 7.3% compared with a body weight reduction of 6.9% in those aged under 60 years. Both groups spent a similar amount of time within the obesity service, on average 33.6 months for those 60 years and over, and 41.5 months for those younger than 60 years. The hospital-based program used only lifestyle-based changes tailored to each individual patient, focusing on dietary changes, psychological support, and encouragement of physical activity. Most of the patients referred to the obesity service were morbidly obese with a BMI typically over 40.

Immune System Aging as Only Loosely Coupled to the Rest of Aging
https://www.fightaging.org/archives/2020/12/immune-system-aging-as-only-loosely-coupled-to-the-rest-of-aging/

The immune system ages along with everything else in the body, entering the states of immunosenescence and inflammaging. Immunosenescence is a growing ineffectiveness of the immune response, while inflammaging is a constant and inappropriate activation of the immune response. Researchers here make the point that immune aging might be thought of as being only loosely coupled to the rest of aging, as it is possible, for example, for chronic infections such as HIV to bring on aspects of immunosenescence and inflammaging far earlier in life than would otherwise be the case.

Aging has been associated with a myriad of both acute and chronic diseases. At the core of these diseases, the change in the host immune system with age could either have contributed to the cause as it is the host main defence mechanism against foreign pathogens or its functionality being impacted by these diseases and conditions. However, the change in the immune system with age could also be seen as an adaptation process to save resources for the host rather than it being detrimental.

This is because developing competent naïve T cells has only about 1-2% success rate due to the various stringent selection processes. Therefore, biological processes such as thymic involution could be seen as advantageous to the host from an energetic or evolutionary point of view. One of the main arguments that thymic involution is detrimental to the host is due to the reduction of naïve T cells being produced, leading to a narrower repertoire for new antigens and perhaps reduced vaccine efficacy often observed in the elderly, while this may have been a successful programmed process for the shorter-lived humans in the past centuries and before the extended human lifespan has revealed the probable need to reverse this adaptation.

Chronic low-grade inflammation is a commonality between individuals that exhibit chronic stress, obesity, aging, sleep loss, gut dysbiosis, CMV infection, dysregulated immune cell functions, and accumulation of SASP cells such as fibroblasts. Chronic low-grade inflammation is defined as a higher baseline of pro-inflammatory cytokines in the circulation though the source and specific cytokines might differ slightly between these "diseases" in the absence of foreign pathogen infection. In terms of impaired immunity, both human and animal studies have shown that chronic stress reduces various immune functional capacities. The presence of impaired immunity and low-grade chronic inflammation could be the underlying factors that exacerbate pathology in various disease contexts.

Thus, it is important that we redefine and stress that the definition of immunosenescence is the dysfunctionality of the immune system and should encompass some features of low-grade chronic inflammation. Though this phenomenon is often seen in aged individuals, it is also possible in younger adults as it could be "accelerated immunosenescence", especially for T cells, as shown in CMV and HIV seropositive young patients. Even early in life, the impact of CMV can be observed. This highlights that other factors other than chronological age could determine this level of senescence of the immune system, especially for T cells which are prone to proliferation. Overall, rethinking the causing agents and implications of immunosenescence will help shift the perspective that this phenomenon is not attributed to age alone, especially with the global rising rate of obesity and chronic stress of modern-day life in the young.

Using Inflammatory Signaling to Lure Transplanted Stem Cells to Damaged Locations in the Body
https://www.fightaging.org/archives/2020/12/using-inflammatory-signaling-to-lure-transplanted-stem-cells-to-damaged-locations-in-the-body/

Researchers here report on their efforts to improve stem cell therapies by steering the cells to migrate to areas of damage in the body. These cells travel through the body towards regions of inflammatory signaling. The researchers adapted one of these signal molecules to make it unlikely to significantly provoke cells into an inflammatory response, while still being attractive to stem cells. Using this molecule to steer stem cell migration to specific locations results in an improved efficacy of stem cell therapy in animal models, a good demonstration of the potential utility of this approach.

Nearly 15 years ago, researchers discovered that stem cells are drawn to inflammation, a biological "fire alarm" that signals damage has occurred. However, using inflammation as a therapeutic lure isn't feasible because an inflammatory environment can be harmful to the body. Thus, scientists have been on the hunt for tools to help stem cells migrate to desired places in the body. This tool would be helpful for disorders in which initial inflammatory signals fade over time - such as chronic spinal cord injury or stroke - and conditions where the role of inflammation is not clearly understood, such as heart disease.

In the study, the scientists modified CXCL12 - an inflammatory molecule which the team previously discovered could guide healing stem cells to sites in need of repair - to create a drug called SDV1a. The new drug works by enhancing stem cell binding and minimizing inflammatory signaling, and can be injected anywhere to lure stem cells to a specific location without causing inflammation.

To demonstrate that the new drug is able to improve the efficacy of a stem cell treatment, the researchers implanted SDV1a and human neural stem cells into the brains of mice with a neurodegenerative disease called Sandhoff disease. This experiment showed SDV1a helped the human neural stem cells migrate and perform healing functions, which included extending lifespan, delaying symptom onset, and preserving motor function for much longer than the mice that didn't receive the drug. Importantly, inflammation was not activated, and the stem cells were able to suppress any pre-existing inflammation.

The researchers have already begun testing SDV1a's ability to improve stem cell therapy in a mouse model of ALS, which is caused by progressive loss of motor neurons in the brain. Previous studies indicated that broadening the spread of neural stem cells helps more motor neurons survive, so the scientists are hopeful that strategic placement of SDV1a will expand the terrain covered by neuroprotective stem cells and help slow the onset and progressive of the disease.

Sestrin Mediates Some of the Benefits of Calorie Restriction in Flies
https://www.fightaging.org/archives/2020/12/sestrin-mediates-some-of-the-benefits-of-calorie-restriction-in-flies/

The practice of calorie restriction reliably improves health and extends life span in near all species tested to date. Many of the pharmacological and genetic approaches to slowing aging have emerged from studies of the cellular maintenance mechanisms triggered into greater activity by calorie restriction, or the nutrient sensing mechanisms that govern initiation of the calorie restriction response. None of these approaches have yet demonstrated themselves to be any better than the actual practice of calorie restriction, and thus while scientifically interesting, are perhaps not a good point of focus for the growing longevity industry.

The health benefits of dietary restriction have long been known. Recently, it has become clear that restriction of certain food components, especially proteins and their individual building blocks, the amino acids, is more important for the organism's response to dietary restriction than general calorie reduction. On the molecular level, one particular well-known signalling pathway, named TOR pathway, is important for longevity. "We wanted to know which factor is responsible for measuring nutrients in the cell, especially amino acids, and how this factor affects the TOR pathway. We focused on a protein called Sestrin, which was suggested to sense amino acids. However, no one has ever demonstrated amino acid sensing function of Sestrin in a living being."

"Our results in flies revealed Sestrin as a novel potential anti-ageing factor. We could show that the Sestrin protein binds certain amino acids. When we inhibited this binding, the TOR signalling pathway in the flies was less active and the flies lived longer. Flies with a mutated Sestrin protein unable to bind amino acids showed improved health in the presence of a protein-rich diet."

If the researchers increased the amount of Sestrin protein in stem cells located in the fly gut, these flies lived about ten percent longer than control flies. In addition, the increased Sestrin amounts only in the gut stem cells also protected against the negative effect of a protein-rich diet. "We are curious whether the function of Sestrin in humans is similar as in flies. Experiments with mice already showed that Sestrin is required for the beneficial effects of exercise on the health of the animal. A drug that increases the activity of the Sestrin protein might therefore be in future a novel approach to slow down the ageing process."

Senescent Cells and Changes in Systemic Factors in Aging
https://www.fightaging.org/archives/2020/12/senescent-cells-and-changes-in-systemic-factors-in-aging/

Senescent cells accumulate with age in all tissues, and contribute to aging via secreted signals that provoke inflammation and tissue restructuring. This portion of aging is a malfunction of a system that normally aids in regeneration and resistance to cancer. Senescent cell signaling is beneficial in the short term, attracting immune cells to areas of damage that should be policed for potentially cancerous cells, or coordinating the interactions of cells needed to efficiently heal an injury. In these cases, in a young individual, the senescent cells involved are quickly destroyed once their task is complete. It is when this needed destruction falters with age, and signaling becomes constantly present, that the problems start. As researchers examine the changing presence of factors in blood and tissue samples, many of these age-related alterations are traced back to the activity of senescent cells.

Extracellular vesicles (EVs) are membrane bound vesicles which vary from nanometer to micrometer in size and carry a diverse set of factors. Recently, our group investigated how circulating EVs change with age, the cell types responsible, and the response of these factors to rejuvenation therapies. Profiling of EV cargo revealed greater expression of inflammation-associated microRNAs such as miR-146a, miR-21, let-7a, and miR-223 in old plasma EVs compared with young. These microRNAs are predicted to target multiple intracellular signaling cascades which regulate cellular responses to external stimuli.

To determine the cell types responsible for changes in circulating EV microRNAs, we assessed EVs secreted by young and old peripheral blood mononuclear cells (PBMCs) in-vitro as well as plasma EVs isolated from old mice reconstituted with young or old bone marrow. However, EV microRNAs were similar in both models, suggesting that circulating cells have a minor contribution to the microRNAs identified this study. Further investigation into potential cell sources revealed that induction of senescence in-vitro and in-vivo, using gamma irradiation, mimicked the changes observed in old mice such as increased levels of circulating EVs and increased expression of EV associated miR-146a, mIR-21, and let-7a.

Interestingly, senolytic therapy using dasatinib + quercetin (D+Q) reduced the expression of these microRNAs in the plasma of old mice, supporting that senescent cells or the pathways targeted by these compounds contribute to increased expression in the circulation. Collectively, this data demonstrates that aging and cellular senescence leads to increased levels of circulating EVs, and that these EVs impair cellular responses to activation. Pharmacological targeting of senescent cells partially rejuvenated the microRNA profile and functional effects of old plasma EVs.

Senescent cells secrete cytokines, growth factors, and proteases which alter neighboring cell function. This secretome is collectively referred to as the senescent associated secretory profile (SASP) and the adverse effects of senescent cells are largely attributed to this profile. More recent definitions of the SASP have been expanded to include EVs. Secretion of EVs by senescent cells into the circulation could be one mechanism by which senescent cells promote cell dysfunction, as persistent uptake of senescent-EVs may lead to sustained changes in cellular function. Therefore, approaches aimed at targeting senescent cells may help reduce circulating senescent-EV levels and limit the impact senescent cells have on cells throughout the body.

Adipogenic Lineage Precursor Cells Upregulate Osteoclast Function via RANKL, Contributing to Bone Loss with Age
https://www.fightaging.org/archives/2020/12/adipogenic-lineage-precursor-cells-upregulate-osteoclast-function-via-rankl-contributing-to-bone-loss-with-age/

Osteoporosis is the name given to the loss of bone density with age, producing severe consequences in the later stages. The proximate cause is a growing imbalance between the constant activity of osteoblast cells that that create bone and osteoclast cells that break down bone. Researchers here delve into the regulation of osteoclast function, and find a lineage of cells that might be targeted to reduce osteoclast activity in later life. This is a compensatory potential class of therapy, rather than an approach that addresses the root causes of the issue, but nonetheless interesting.

New research has discovered a cell type that governs the way bones form and maintain themselves, opening up a potential target for future therapies for bone disorders like osteoporosis. A rodent study showed that bone marrow adipogenic lineage precursors (MALPs) play a distinct role in the way bones remodel themselves. Defects in this process are the key issue at play in osteoporosis, so a therapy using these MALP cells to better regulate bone remodeling could result in better treatments.

Healthy bone maintenance is a balance between osteoblasts, which secrete the materials necessary to form new bone, and osteoclasts, which absorb old bone material to make way for the new. A disruption in this balance one way or the other can result in unhealthy bone. In the case of osteoporosis, overactive osteoclasts eat away at bone faster than it can be reformed, resulting in bones that are less dense and more susceptible to fracture. The general consensus among scientists was that osteoblasts and osteocytes, the cells within fully-formed bone, were the ones that kicked off the production of osteoclasts to begin the remodeling of bone. On the other hand, the role of adipocyte lineage cells, such as MALPs, in regulating the resorption of bone was not known.

MALPs are the precursors for adipocytes that carry fats, called lipids, inside bone marrow. Recent studies better cleared up how MALPs appear to factor in bone turnover. They showed that MALPs, but not osteoblast or osteocytes, have cell-to-cell contact with osteoclasts. Additionally, using advanced sequencing techniques at a single cell level, researchers found that MALPs secrete RANKL, a protein essential for forming osteoclasts, at a high level.

With that information, researchers studied mice with RANKL deficiencies in their MALPs. From the point those mice turned a month old, the researchers saw 60 to 100 percent higher density of the spongy components of long bones (like the femur) and vertebrae, something the researchers qualified as "a drastic increase" compared to typical mouse bone mass. Since the osteoblasts and osteocytes continued to work as they always do, it would seem that MALPs and their RANKL secretions have been pinpointed as the main driver of osteoclast function and the absorption of existing bone.

Longevity Industry 1.0, the Book
https://www.fightaging.org/archives/2020/12/longevity-industry-1-0-the-book/

The Longevity.International group has for the past few years been turning out sizable documents on a regular basis as a part of an attempt to exhaustively catalog groups in academia, industry, government, and venture capital that are either working on or supporting the development of treatments that have the potential to slow or reverse aging. A perspective and digest of this work has now emerged in book form, and seems worth a look for those already passingly familiar with the community.

In "Longevity Industry 1.0 - Defining the Biggest and Most Complex Industry in Human History", seasoned Longevity industry professionals Dmitry Kaminskiy and Margaretta Colangelo distill the complex assembly of deep market intelligence and industry knowledge that they have developed over the past 5 years into a full-scope understanding of the global Longevity Industry, showing the public exactly how they managed to define the overwhelmingly complex and multidimensional Longevity Industry for the first time, and how they created tangible framework for its systematization and forecasting.

The book features first of its kind coverage of entirely new segments and sectors of the rising Longevity Industry, including Longevity Politics and Governance, the Longevity Financial Industry (including coverage of AgeTech, WealthTech, FinTech, and the coming rise of new financial instruments and derivatives), the current state and forecasts on the Global Industrialization of Longevity to Scale, and an overview of the near-future trajectory of the Longevity Industry's evolution 2020-2025.

The Distinct Mechanisms of Aging Interact with One Another
https://www.fightaging.org/archives/2020/12/the-distinct-mechanisms-of-aging-interact-with-one-another/

Aging has a number of distinct root causes, but they do not proceed in isolation. Cell and tissue damage of one sort interacts with cell and tissue damage of other sorts, and so too do all of the downstream consequences of that damage. Aging is a web of connected issues, all making each other worse as they progress. Degenerative aging accelerates in pace over time precisely because of this behavior, in which damage and dysfunction speeds up the accumulation of more damage and dysfunction. The authors of the open access paper here illustrate this principle by taking mitochondrial dysfunction as a starting point and examining how it interacts with other known mechanisms of aging.

The role of mitochondrial dysfunction in aging is well documented. The primary hallmarks of aging are defined as unequivocally deleterious to the cell. This means that proper functioning of these processes is important for the viability of the cell and the dysfunction that occurs with age leads to cellular damage. Mitochondrial dysfunction interacts with each of these primary hallmarks, thus leading to progression of the aging process.

The nine cellular and molecular hallmarks of aging are divided into three groups; (a) the primary hallmarks, (b) antagonistic hallmarks, and (c) integrative hallmarks. The primary hallmarks, which are unequivocally deleterious to the cell, include genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis. The antagonistic hallmarks, which are beneficial at low levels but at high levels become deleterious, are deregulated nutrient sensing, cellular senescence, and mitochondrial dysfunction. Finally, the integrative hallmarks, affecting tissue homeostasis and function, are stem cell exhaustion and altered intercellular communication. These hallmarks of aging have been presented throughout various research disciplines as nine separate hallmarks, and, while possessing crosstalk, are still considered largely independent. In this review, we provide evidence of the interplay between hallmarks, by highlighting one, mitochondrial dysfunction, and how it interacts with all others.

The hallmarks of aging connect to and influence one another. For instance, cellular senescence can be induced by genomic instability or telomere attrition and epigenetic alternations can lead to genomic instability. It is hence evident that the hallmarks of aging are not discrete entities as how are often presented, but instead operate in a large and tightly connected network. Targeting one factor of this network can result in affecting other hallmarks and thus influence the whole network of aging.

Although this complicates our interpretation of anti-aging interventions and requires a more holistic approach, it also opens opportunities for treatment options that not only target one hallmark but in fact act on the entire, or at least a large section of the network. In relation to the phylogenetic tree of life, while the exact details of the hallmarks of aging may differ, the main commonality that unifies aging across all species is the fact that all their hallmarks interconnect. Taking the entirety of this network into account will benefit the aging research community, and ultimately allow for a greater understanding of the aging processes and the progression of age-related disease.

PDK1 Inhibition Reverses Cellular Senescence
https://www.fightaging.org/archives/2020/12/pdk1-inhibition-reverses-cellular-senescence/

Cells become senescent in response to damage, signaling of other senescent cells, or on reaching the Hayflick limit to cell replication. Senescent cells cease to replicate, secrete a potent mix of inflammatory signals, and near all self-destruct or are destroyed by the immune system. Unfortunately, some escape this fate, and so senescent cells accumulate with age to cause chronic inflammation, tissue remodeling, and age-related disease. A few years ago, researchers discovered a way to adjust splicing factors to reverse cellular senescence, allowing cells to replicate once again. Here, another approach is outlined, which may or may not work via similar underlying mechanisms. I remain of the mind that this isn't a useful path to therapy, as a significant fraction of senescent cells become senescent for a good reason, in that they are damaged and potentially cancerous. It is better, I think, to focus on selective destruction via senolytic therapies rather than attempts to rehabilitate senescent cells.

Cells respond to a variety of factors, such as oxidative stress, DNA damage, and shortening of the telomeres capping the ends of chromosomes, by entering a stable and persistent exit from the cell cycle. This process, called cellular senescence, is important, as it prevents damaged cells from proliferating and turning into cancer cells. But it is also a natural process that contributes to aging and age-related diseases. Recent research has shown that cellular senescence can be reversed. But the laboratory approaches used thus far also impair tissue regeneration or have the potential to trigger malignant transformations.

Researchers used an innovative strategy to identify molecules that could be targeted for reversing cellular senescence. The team pooled together information from the literature and databases about the molecular processes involved in cellular senescence. To this, they added results from their own research on the molecular processes involved in the proliferation, quiescence (a non-dividing cell that can re-enter the cell cycle), and senescence of skin fibroblasts, a cell type well known for repairing wounds. Using algorithms, they developed a model that simulates the interactions between these molecules. Their analyses allowed them to predict which molecules could be targeted to reverse cell senescence.

They then investigated one of the molecules, an enzyme called PDK1, in incubated senescent skin fibroblasts and three-dimensional skin equivalent tissue models. They found that blocking PDK1 led to the inhibition of two downstream signalling molecules, which in turn restored the cells' ability to enter back into the cell cycle. Notably, the cells retained their capacity to regenerate wounded skin without proliferating in a way that could lead to malignant transformation. The scientists recommend investigations are next carried out in organs and organisms to determine the full effect of PDK1 inhibition. Since the gene that codes for PDK1 is overexpressed in some cancers, the scientists expect that inhibiting it will have both anti-aging and anti-cancer effects.