Fight Aging!

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Contents

• Age-Related Dysfunction in Cellular Metabolism Substantially Impacts the Immune System
• Procaine as an Example of the Slow Reclassification of Known Small Molecule Drugs as Geroprotectors
• A Bidirectional Relationship Between Cellular Senescence and Immune System Aging
• Phase 2 Clinical Trial Results for a First Generation Stem Cell Therapy to Treat Frailty
• 95% of Centenarians are Frail
• A Reduced Memory B Cell Population in Older People Impairs Immune Response
• Cell Therapy Improves Tendon Regeneration in Sheep
• Poor Diet and Lack of Exercise Correlate with Risk of Cognitive Decline and Dementia
• Reviewing the Ability of Calorie Restriction to Slow Aging
• The Role of Amyloid-β in Neurodegeneration Inside Cells versus Outside Cells
• The Age-Related Decline of Mitophagy as a Contributing Cause of Stem Cell Dysfunction
• Signs of Endothelial Inflammation in Human Neurodegeneration
• Osteopontin in Blood Samples as a Biomarker of Aging
• A Mechanism by which Amyloid-β Can Cause Degeneration of Synapses
• A Meta-Analysis of the Ability of Aerobic Exercise to Improve Memory and Executive Function

Age-Related Dysfunction in Cellular Metabolism Substantially Impacts the Immune System
https://www.fightaging.org/archives/2021/08/age-related-dysfunction-in-cellular-metabolism-substantially-impacts-the-immune-system/

Most of what to my eyes are less promising lines of research into the treatment of aging are focused on manipulation of cellular metabolism. These approaches, such as targeting the mTOR pathway, largely derive from the study of calorie restriction and the cellular response to stress that is brought on by lack of nutrients. Calorie restriction extends average and maximum life span considerably in short-lived species, up to 40% in mice, for example. It increases the efficiency of cellular maintenance processes and makes cells more frugal in other ways. The impact of aging is slowed, as molecular damage accumulates less rapidly. Yet in long-lived species such as our own, short-term benefits are evident, but the practice of calorie restriction doesn't change human life span by a large amount.

It is thought by some in the research community that many of the changes that take place in short-lived mammals in response to nutrient stress have already evolved to operate consistently in long-lived mammals such as ourselves, precisely in order to make us long-lived. Calorie restriction produces such sweeping changes in the operation of cellular metabolism that researchers make only slow progress towards picking out the areas of importance, or towards expanding the catalog of interactions between pathways and mechanisms and aging.

Cellular metabolism becomes more dysfunctional with age in ways that can be assessed. As today's open access paper notes, some of these changes appear to cause further dysfunction in the immune system. Thus attempting to compensate for age-related metabolic issues by intervening in the mTOR pathway can improve immune function in old people to some degree, and it is believed that similar results can be obtained via other metabolic adjustment. It is worth noting that this is also true of exercise or the practice of calorie restriction! How and why does this improvement in immune function happen? The connections are complicated and still comparatively poorly explored.

Moving away from manipulation of metabolism towards the more direct approach of damage repair, one can improve metabolism by removing lingering senescent cells, a form of tissue damage. The presence of senescent cells disrupts cellular metabolism via the senescence-associated secretory phenotype, signaling that changes surrounding cell behavior for the worse. Removing damage that causes detrimental metabolic change seems a more promising approach than adjusting factors inside cells to try to minimize their response to that damage. Indeed, senescent cell clearance compares very favorably to mTOR inhibition in animal studies.

Targeting Aging: Lessons Learned From Immunometabolism and Cellular Senescence

Two hallmarks of aging, mitochondrial dysfunction and dysregulated nutrient sensing, are tightly associated with metabolic alterations. Increasing research is investigating the role of metabolism in controlling longevity. Three metabolic and nutrient sensing pathways, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and sirtuins, are under investigation as potential targets for aging.

Although all systems are affected, the hallmarks of aging substantially impact the immune system. It is well known that aging leads to progressive declines in innate and adaptive immunity. This immunosenescence is accompanied by chronic low-grade inflammation, or inflammaging. This results in increased susceptibility to infections, reduced response to vaccination, and increased prevalence of cancers, autoimmune and chronic diseases. Not surprisingly, given that deregulated nutrient sensing and mitochondrial dysfunction are hallmarks of aging, markers of inflammaging also coincide with markers of metabolic dysfunction.

Recent research has highlighted the importance of mitochondrial function and cellular metabolism in controlling immune cell function. Indeed, immunometabolism is critical for proper immune function. What remains to be fully explored is how age and age-associated factors, such as senescent cell accumulation, impact immunometabolism and therefore immune function. This research gap represents a potentially fruitful target for immune modulation in older adults.

Interventions that target dysregulated metabolism or senescence may prove fruitful for improving aged immune responses, leading to additional protection when dealing with infection. In fact, it has been demonstrated that low dose TORC1 inhibition in older adults decreased risk of all infections, upregulated antiviral immunity, and improved influenza vaccination responses. Although further research is necessary to fully elucidate the mechanisms by which metabolic changes with aging contribute to T cell dysfunction, current metabolic therapeutics may prove beneficial for targeting the aging immune system.

Furthermore, targeting senescent cells may also improve immunometabolism with aging. Senolytics, drugs that target senescent cells, have shown great promise with treating age-related diseases and phenotypes. With age, there is increased insulin resistance driven by dysfunction in adipose tissue. Senescent adipocyte progenitor cells were found to be the root cause of dysfunction and when cleared with senolytic treatment, insulin resistance is reversed. Interestingly, many immune cells (including T cells, B cells, and NKT cells), are thought to exacerbate insulin resistance. Taken together, the ablation of the senescence-associated secretory phenotype using senolytics could possibly reverse the deleterious activity of these immune cells which could be beneficial beyond insulin resistance. Furthermore, senolytics may reduce CD38 expressing macrophages and preserve NAD+ levels with aging, offering a promising strategy to enhance metabolic fitness with age.

Procaine as an Example of the Slow Reclassification of Known Small Molecule Drugs as Geroprotectors
https://www.fightaging.org/archives/2021/08/procaine-as-an-example-of-the-slow-reclassification-of-known-small-molecule-drugs-as-geroprotectors/

The classification of "geroprotector" is fairly recent. In present use, it largely means a small molecule drug that can favorably target mechanisms known to be associated with aging. Some of these small molecules come with evidence for a slowing of aging in animal studies. A very few can boast evidence for the same from human trials. Most geroprotectors target stress response mechanisms, those involved in calorie restriction, but senotherapeutic drugs that reduce the burden of cellular senescence might also be classed as geroprotectors.

That a drug can be called geroprotective is no guarantee that it is actually useful, of course. Effect size matters! Aspirin can reasonably be classified as a calorie restriction mimetic drug, and there is evidence for reduced mortality in old people that is mixed but better than that for most putative geroprotectors. We all know that aspirin isn't going to help us change the shape of a human life to any meaningful degree, and most geroprotectors are probably worse than aspirin in terms of reliability and size of effect. Just because a mechanism can be linked to a small molecule doesn't mean that the outcome in human medicine will be anything to write home about.

Nonetheless, given the new classification of geroprotector, there are now growing databases of actual and potential geroprotectors, assembled from the literature where there is any evidence for interaction with areas of metabolism connected to aging, or animal or human data for signs of slowed aspects of aging. Some of the many drugs that have interested researchers in connection with aging, from time to time over the past century or more, coming and going as fashionable targets for scientific programs, can now be declared potential geroprotectors. Any specific case usually provides at least some interesting insight into just how slow and lengthy is the path to understanding any given drug, and how challenging it is to assess modest effect sizes in the matter of aging.

Procaine - The Controversial Geroprotector Candidate: New Insights Regarding Its Molecular and Cellular Effects

Procaine was synthesized in 1905 and introduced in clinical practice as Novocain, soon becoming a local anesthetic prototype. Around the 1950s, a large number of accumulated data emphasized the surprising diversity of nonanesthetic effects exerted by procaine, which came to the attention of various medical research schools in Eastern and Western Europe, many doctors exploring, regardless of borders, the beneficial properties of procaine. Between 1946 and 1956 researchers described a significant number of procaine beneficial actions exerted on cellular functions and metabolism, following long-term treatment in low doses, highlighting its "rejuvenating" effects, and developed Gerovital H3 (GH3) - an original procaine-based pharmaceutical formulation. Due to these findings, procaine which was known only for its anesthetic properties became one of the most disputed medical developments of the sixties and seventies in the field of "anti-aging" therapies.

Recent progresses in the field of aging research led to the development of a new class of drugs - geroprotectors, with the ability to target fundamental mechanisms of aging common to multiple age-related diseases, such as response to oxidative damage, inflammation, hypermethylation, cellular senescence, and autophagy. Researchers have established the first public database of geroprotectors that indexes the most relevant experiments involving over 200 well-established geroprotectors or possible candidates that could extend the healthy lifespan and repair or reduce aging-related damage in model organisms.

As primary selection criteria for the potential geroprotectors, the following characteristics were recognized: (1) the ability to increase lifespan; (2) the capacity to ameliorate molecular, cellular, and physiological biomarkers to a younger state or slow the progression of age-related change of these markers; (3) a therapeutic lifespan-extending dose of geroprotector, which should be several orders of magnitude less than the toxic dose; and (4) the capacity to improve the health-related quality of life of the patient, from a physical, mental, emotional, and social viewpoint. The compliance of procaine with most of these criteria would allow it to be a potential "geroprotector" candidate.

Although GH3 was internationally launched in 1956, simultaneously with the development of the Free Radical Theory of Aging, the study of the antioxidant action of procaine and GH3 was documented only after 1980, in various experimental designs, which proved its capacity of limiting the generation of reactive oxygen species (ROS) and lipid peroxidation. Besides its antioxidant, cytoprotective, anti-inflammatory, and antiatherogenic effects, at cellular and molecular levels, procaine has multiple targets, supporting a large number of potential "geroprotective" effects. Older and more recent data revealed that procaine and its metabolites modulate several biochemical and cellular processes like mitochondrial structure and function.

A Bidirectional Relationship Between Cellular Senescence and Immune System Aging
https://www.fightaging.org/archives/2021/08/a-bidirectional-relationship-between-cellular-senescence-and-immune-system-aging/

The pace of age-related loss of function and consequent mortality accelerates over time, picking up particularly rapidly in later life. This is characteristic of systems in which multiple processes feed into each other. A causes B, but B also makes A worse. In the biology of aging there are many more than two processes at work, but the authors of today's open access paper picked two areas of aging in order to examine their bidirectional relationship. Firstly the accumulation of senescent cells, and secondly immunosenescence, the age-related decline of immune system function.

Cells become senescent constantly in the body, largely as a result of somatic cells reaching the Hayflick limit on replication. Wound healing, potentially cancerous molecular damage, and the signaling of other senescent cells are also relevant causes of cellular senescence. Some senescent cells self-destruct, while others are destroyed by the immune system. That immune surveillance of senescent cells becomes slower and less effective as the immune system falls into immunosenescence in later life, allowing for senescent cell accumulation.

Equally, senescent cells secrete inflammatory, disruptive signaling that causes chronic inflammation as well as harmful changes in cell behavior in the hematopoietic system responsible for generating new immune cells. Inflammation also contributes to the involution of the thymus, where T cells mature, accelerating the decline of adaptive immune function by reducing the supply of new T cells. Further, immune cells themselves become senescent in increasing numbers, a response to the burden of too much cell replication and too few replacement cells.

It is plausible that these mechanisms indicate that the progression towards immunosenescence leads the accumulation of senescent cells in the early dance of cause and effect in mid-life, before everything in the body becomes so broken that it is hard to say what is most responsible. It is very hard to assign appropriate blame to interacting mechanisms of aging without a way to eliminate one of them at a time and observe the results, however. Intuition is rarely useful. With the advent of senolytic therapies to clear senescent cells, it should be possible to say with certainty at some point as to whether immunosenescence is upstream of cellular senescence in aging. Few researchers are looking at the details of cellular senescence or immune system decline at early stages in the aging process, however.

Cellular senescence in lymphoid organs and immunosenescence

The immune system is a complex network of cells and tissues working in coalition to maintain the health of an organism. It not only clears foreign pathogens, but also helps to maintain the integrity of the organism by clearing away dead or dysfunctional cells. Like any other system, the immune system changes with age and experiences gradual deterioration. Improving our understanding of this phenomenon is of great significance. Aging of the immune system is also one of the major factors that accelerates the deterioration of an organism, as its dysfunction not only fails to elicit a strong immune response against invading pathogens but also drives the accumulation of undesirable and malfunctioning cells.

From an evolutionary perspective, cellular senescence is widely considered to be a protective mechanism to prevent stressed and damaged cells from becoming deleterious to the body. Like most things optimized by evolution, cellular senescence is not of much concern to the younger body capable of reproduction while the older body, past its reproductive prime, is adversely affected by it. The fitness benefits that cellular senescence provides to younger, reproductively active animals, such as preventing cancer, mitigating the progression of fibrosis, and promoting optimal wound healing, have helped the phenomenon survive the arduous tests of natural selection over the millennia. Unfortunately, in almost an antagonistically pleiotropic manner, accumulation of senesent cells (SnCs) is very detrimental to the older body. Specifically, SnCs secrete various factors classified together as the senescence-associated secretory phenotype (SASP) which cause instability and dysfunction in their surrounding environment.

The interactions between SnCs and the immune system run in both directions, with the immune system surveilling and clearing the SnCs; while the SnCs frequently impede the function, and in some contexts, generation of immune cells. In young and healthy individuals, the immune system can rapidly clear SnCs after their induction, which prevents them from significantly accumulating and causing adverse effects. In older individuals, this turnover is slow and leads to the accumulation of SnCs. It has been demonstrated that accumulation of SnCs is accelerated upon impaired immune surveillance. Since advancing age is associated with impairment in immune function, the decline in the turnover of SnCs with age can, at least partially, be attributed to this impediment. Despite multiple studies demonstrating various mechanisms via which SnCs could evade immune clearance, the impact of aging on immune evasion of SnCs is not yet completely understood.

Of note, SnCs have been shown to cause stem cell exhaustion, and dysfunction. This is of great relevance and importance to the topic of immunosenescence because senescence, exhaustion, and dysfunction of hematopoietic stem cells (HSCs) causes myeloid skewing and a decrease in the production of immune cells which may be one of the underlying causes of age-related immunosenescence. However, even at an organ level, the age-associated changes that contribute to immunosenescence are multifaceted with a wide variety of undesirable phenotypic manifestations. Thus, it would be ill-advised to address each of these problems individually. A more feasible and effective way to deal with immunosenescence would be to tackle the fundamental aspects of aging that drive immunosenescence. With studies showing that clearing SnCs can rejuvenate entire tissues and organs of the aged immune system, cellular senescence is certainly one such fundamental aspect, which has the potential to address immunosenescence.

Phase 2 Clinical Trial Results for a First Generation Stem Cell Therapy to Treat Frailty
https://www.fightaging.org/archives/2021/08/phase-2-clinical-trial-results-for-a-first-generation-stem-cell-therapy-to-treat-frailty/

First generation stem cell therapies are simple in concept, a matter of transplanting cells taken from person A into person B in the hope of producing benefits, but the implementation hides a great deal of complexity. Tissue is provided by donors, cells are selected from that tissue, the resulting population of cells is expanded in culture, their behavior and state may be modified in simple ways via the addition of factors, the cells are manufactured into doses that can be frozen, and then injected into patients. For every one of those steps there are many, many different approaches, refinements, and epicycles.

It remains poorly understood as to why the outcomes of this class of therapy are so variable, even for clinics practicing what seem to be similar methodologies. It is hard to say why the (allegedly) more successful implementations are in fact more successful, particularly since most of them are owned by individual clinics and will never be the subject of formal clinical trials.

Near all such stem cell transplants reliably reduce chronic inflammation. This, at least, is fairly consistent across approaches. This outcome occurs due to signaling by the transplanted cells, and can last for months. The cells themselves near all die much more rapidly than that, though it is the case that a few clinics and approaches claim a meaningful degree of cell engraftment and survival. Beyond reductions in chronic inflammation, lasting improvement in tissue function or a regeneration of damaged tissue is a goal, but not one that is reliably achieved, considering this field as a whole.

A reduction in chronic inflammation makes age-related frailty an attractive target for stem cell therapies, characterized as it is by systemic inflammation. There is a great deal of evidence for continual inflammation to be an important cause of loss of muscle mass and strength, as well as the disruption of function in many other tissues. Thus a number of groups have attempted the expensive process of formalizing a stem cell therapy implementation in order to take it into clinical trials to treat frailty. Today's example appears modestly successful, though it is always worth comparing the outcomes of this sort of study with those that have been achieved via structured exercise programs and strength training regimens designed for the elderly.

Longeveron Announces Topline Results of Phase 2b Study of Lomecel-B for Aging Frailty

Longeveron, a clinical stage biotechnology company developing cellular therapies for chronic aging-related and life-threatening conditions, today announced results from the Company's Phase 2b trial titled: A Phase 2b, Randomized, Blinded and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B Infusion in Patients With Aging Frailty (the "Phase 2b trial"). Lomecel-B is a proprietary allogeneic product comprised of medicinal signaling cells (MSCs) from the bone marrow of adult donors and culture-expanded in Longeveron's current good manufacturing practice (cGMP) cell processing facility. The Phase 2b trial evaluated the safety and efficacy of a single peripheral intravenous infusion of four different doses of Lomecel-B cell therapy: 25 million (n=37), 50 million (n=31), 100 million (n=34) and 200 million (n=16) cells. Results were compared to placebo (n=30), on signs and symptoms of Aging Frailty, including mobility and exercise tolerance.

The main inclusion criteria for entry into the trial were subjects 70-85 years of age, a screening 6 minute timed walk distance of between 200 to 400 meters, a Canadian Health and Safety Assessment (CHSA) Clinical Frailty Scale score of 5 (mildly frail) to 6 (moderately frail), and a minimum serum TNF-α of ≥ 2.5 pg/mL. The primary analysis compared the change from baseline in six minute timed walk distance for the four Lomecel-B cohorts to the placebo cohort at Day 180. There were statistically significant increases in the highest 3 doses and no significant changes in the placebo or lowest dose of Lomecel-B (the following increases in 6 minute timed walk distance were observed: 25 million = 7.8 meters; 50 million = 35.8 meters; 100 million = 24.9 meters; 200 million= 49.3 meters; placebo = 8.0 meters).

"Improving physical function in older adults with frailty is one of the primary goals in geriatric medicine. The fact that patients enrolled in this study, with an average age of 75 and with clear mobility limitations, showed 6-month and 9-month placebo-adjusted increases in walking distance of 40 meters and 63 meters, respectively (at the 200 million cell dose), is significant for a number of reasons. Frailty is associated with poor clinical outcomes and high healthcare utilization and being able to improve and extend walking distance suggests preservation of function and potentially independence."

95% of Centenarians are Frail
https://www.fightaging.org/archives/2021/08/95-of-centenarians-are-frail/

Survival to 100 years of age is a rarity at the present time, but if the present slow upward trend in life expectancy continues, most people born today will live to 100 or more. That trend will, of course, not continue as-is. The past trend was due to incidental effects of public health measures and general progress in medicine on the mechanisms of aging. The trend in life expectancy will leap upwards with the advent of rejuvenation therapies that deliberately target the reversal and repair of those mechanisms. But that is a topic for another post.

Here, let us focus on what actually happens at the present time to people in the last stages of aging. I think it is important to look at the reality of the situation, as in some circles, centenarians are held up as exemplars of health in later life, and the goal of medicine put forward as upholding the slow trend of increased life expectancy, thereby enabling more people to follow the same path. This is a terrible goal. Centenarian health is not good. As today's open access paper shows, near all centenarians are frail. Frailty is a life-limiting set of circumstances, caused by a high burden of the cell and tissue damage that lies at the root of aging. Frailty manifests as physical weakness, dependency, vulnerability to infection, cognitive decline, and a high mortality rate. No-one would choose to be frail, given the option. Mere survival should not be held up as an exemplar of health.

The goal of developing rejuvenation therapies is maintenance of health, the elimination of suffering and limitations such as frailty, cancer, cardiovascular disease, and so forth. Increased healthy life span, ultimately far beyond present human capabilities, will be a happy side-effect of keeping the human machine in good running condition. Rejuvenation is just another name for preventative maintenance sufficient for good operation: identify the damage that limits capabilities, and remove it before it causes major breakage. That is a lot more complicated in a mammal than it is in a car, but the concept is the same, and it will work just as well. If the entire field of longevity science turns into low-expectation-value efforts to modestly slow aging with the goal of making more frail centenarians, then we will have missed the point of the exercise, and missed the opportunity to achieve a great advance in the quality of life for all of humanity.

Age- and Gender-Specific Prevalence of Frailty and Its Outcomes in the Longevous Population: The Chinese Longitudinal Healthy Longevity Study

Based on the Chinese Longitudinal Healthy Longevity Study (CLHLS, 2008-2018), individuals aged ≥ 65 years having complete data of frailty were recruited. The present study reported the prevalence of pre-frailty and frailty among the population with a mean age of 85 years, which were 54.1 and 26.3%, respectively. Females were predominant among frail population in all age groups whereas males were dominant among pre-frail individuals aged ≥ 80 years. Both pre-frailty and frailty were strongly associated with multiple adverse outcomes. Males and the young-old (younger than 80 years) were the most susceptible to the risk of mortality.

Healthy aging is an important goal of the public health in the 21st century. However, a huge gap exists between longer life and healthy aging. The present study indicated the high prevalence of pre-frailty and frailty among the Chinese longevous population, which is consistent with the results from 1,253 centenarians in the 5-COOP study countries (Japan, France, Switzerland, Sweden, and Denmark). It demonstrated that the heavy burden of frailty among the longevous population was globally substantial. Notably, only 5% of centenarians and 11.1% of nonagenarians were non-frailty in the present study. Similar results were observed among centenarians in the 5-COOP countries.

Additionally, the present results comprehensively demonstrated the association between pre-frailty, frailty, and the risk of multiple adverse outcomes. It implies not only the high consumption of healthcare resources of the frail elderly, but also the suffering of patients themselves. Hence, the epidemic of frailty could be considered as one of the great barriers of healthy aging.

A Reduced Memory B Cell Population in Older People Impairs Immune Response
https://www.fightaging.org/archives/2021/08/a-reduced-memory-b-cell-population-in-older-people-impairs-immune-response/

The age-related decline of the immune system is complex. There are many facets to the issues of increased systemic inflammation and reduced immune competence. Here, researchers show that a necessary population of memory B cells is reduced with age, and this impairs the ability of the immune system to respond to novel threats. Clearing the entire B cell complement has been attempted in mice, and shown to improve function. B cells regenerate rapidly following clearance, even in old animals. It is as yet unknown as to how that approach interacts with the dysfunction described here, but B cell clearance does address the problem of an accumulation of dysfunctional age-associated B cells.

Immunological memory is the ability of our immune system to remember previously encountered pathogens. Infections are rare in adults thanks to their large repertoire of specific memory T cells and memory B cells generated by previous antigenic experiences. In the elderly, susceptibility to infections increases again. We focused our attention on B cells that change with age in number and type. As a result of infection or vaccination, B cells become memory B cells (MBCs) and plasmablasts (PBs) able to produce high affinity antigen-specific antibodies. MBCs can be identified by the expression of the CD27 marker. The intensity of expression of CD27 defines two populations, CD27dull and CD27bright MBCs.

We show that the elderly have a significant reduction of CD27dull memory B cells, a population that bridges innate and adaptive immune functions. CD27bright MBCs are generated exclusively by a T cell-dependent mechanism and under a strong selective pressure by an antigen. Compared to children, elderly individuals have more CD27bright MBCs. Taken together, this suggests that their immune system may be equipped to react against well-known antigens but has a reduced ability to respond to new pathogens. Moreover, after in vitro stimulation, B cells from older individuals produced significantly fewer antibodies compared to younger individuals.

Cell Therapy Improves Tendon Regeneration in Sheep
https://www.fightaging.org/archives/2021/08/cell-therapy-improves-tendon-regeneration-in-sheep/

Researchers here move from rodents to sheep in testing the ability of a comparatively simple autologous cell therapy to improve regeneration following tendon injury. The results appear much the same in both species, which suggests that human trials will produce positive results. This approach will join a few other cell therapies aimed at tendon repair and tested in human trials over the past twenty years. The field moves slowly, like much of medicine.

In the search for new and better ways to heal injured tendons, the medical world is looking closely at regenerative therapies. In particular, autologous adipose micrografts (AAMGs) and stromal vascular fraction (SVF) are showing promise. SVF, derived from adipose tissue, contains heterogeneous cell populations including stem cells and immune cells involved in regeneration. In a previous study on rats, AAMGs and SVF improved tendon healing in 60 percent to 70 percent of treated animals. The purpose of a new study was to evaluate the effects of AAMG in sheep with tendinopathy, as larger animals are more comparable to humans than are rodents.

This is also the first study on an animal model employing a mechanical fat breakdown system as an alternative to enzymatic digestion to isolate the SVF. This procedure is able to maintain the microenvironment of the perivascular niche, while at the same time removing any pro-inflammatory factors. The residual SVF contain pericytes that are able to gradually convert into activated adipose stem cells.

The team carried out the study by inducing tendinopathy in both common calcaneal tendons (CCT) of 16 female sheep. Tendinopathy is a breakdown of collagen in a tendon, resulting in burning pain, reduced flexibility and limited range of motion. Four animals were assigned to a non-treated group as a control. Each of the other 12 sheep had one CCT injected with AAMG, while its contralateral CCT was left untreated. At 8 weeks after treatment, the treated group showed a final tendon diameter (9.1 ± 1.4 mm) and a hardness expression (62%) that were similar to the original healthy tendon (8.1 ± 1.1 mm; 100%), with a significant recovery compared with the control group (9.5 ± 1.7 mm; 39%). Moreover, histological analysis of the treated group revealed an improvement in the fiber orientation score, fiber edema score, infiltrative-inflammatory process, and necrosis score compared with control group.

Poor Diet and Lack of Exercise Correlate with Risk of Cognitive Decline and Dementia
https://www.fightaging.org/archives/2021/08/poor-diet-and-lack-of-exercise-correlate-with-risk-of-cognitive-decline-and-dementia/

It is not surprising to find data showing that a poor diet and lack of exercise correlated with an increased risk of later neurodegeneration and dementia. Plenty of studies exist to note that correlation. The question is the degree to which it is correlation versus causation. There are good reasons to believe that regular exercise slows the onset of neurodegeneration, quite clear mechanistic links that are demonstrated to be causal in animal studies. Equally, a poor diet and lack of exercise correlate with many other potential contributing factors in human populations, not least of which is frailty and other manifestations of aging. So to what degree do these correlations in human data reflect protective effects versus the tendency of those who are most affected by aging, and therefore most likely to decline more rapidly, to eat poorly and exercise little?

New research has found that both diet and exercise can influence the risk of cognitive decline (CD) and dementia by potentially influencing hippocampal neurogenesis long before their onset. The investigation studied how the blood of participants with and without CD and dementia could influence hippocampal neurogenesis in laboratory settings and whether diet and exercise were important factors. Specifically, blood samples of 418 French adults over the age of 65 were collected 12-years prior to CD and dementia diagnosis and tested on human hippocampal stem cells. Additionally, information on each participant's sociodemographic, lifestyle, and clinical data were collected and incidence cognition status and dementia were measured every 2 to 3 years over a 12-year period.

Over the course of the study, the researchers established that 12 years prior to diagnosis, both CD and Alzheimer's were associated with levels of neural stem cell death. The team also found that exercise, nutrition, vitamin D levels, carotenoid and lipid levels are all associated with the rate at which cells die off. Furthermore, physical activity and nutrition were key factors that then also determined CD status. Specifically, researchers found that reduced physical activity and increased malnutrition both increased cell death which in turn increased the risk for future CD.

While previous studies have established that diet and exercise have some protective effects against CD and dementia, these roles have been poorly understood at the neurobiological level. To date, studies on animals have shown how diet and exercise can directly influence hippocampal neurogenesis, potentially explaining how exercise and diet may biologically exert their effects, but this study sheds further light on this in the context of a human model. "If an individual displays an increase in their levels of cell death during differentiation (when neural stem cells are becoming neurons), we can look at this as a potential warning sign of CD. Conversely, a decrease in levels of cell death during proliferation (the process by which a single cell divides into a pair) and reduced hippocampal progenitor cell integrity could be viewed as a predictor for Alzheimer's disease and vascular dementia, respectively."

Reviewing the Ability of Calorie Restriction to Slow Aging
https://www.fightaging.org/archives/2021/08/reviewing-the-ability-of-calorie-restriction-to-slow-aging/

Calorie restriction is the most studied means to slow aging, and from this numerous lines of work have emerged, each focused on one small subset of the sweeping changes in metabolism that occur in response to a lowered intake of nutrition. Lack of nutrients puts stress on cells and organisms, and this has been the case since the emergence of life. The response to calorie restriction thus has ancient evolutionary origins, and is quite similar across all eukaryotic species investigated to date. The one big difference is that maximum life span is greatly extended in short-lived species, but not in long-lived species such as our own. Why this is the case is a matter still under investigation, and an interesting scientific puzzle, given that so many of the short-term benefits of calorie restriction are more or less the same in mice and humans.

Among the multiple alterations that have a profound impact on aging, the nutrient sensing cell pathways have recently captured much interest thanks to their potential as therapeutic targets in the prevention of age-related diseases, and the extension of the healthy life-span. The nutrient sensing pathways are mainly regrouped in the IGF (insulin-like growth factor)/insulin, the TOR (target of rapamycin), and the AMPK (AMP-Activated Protein Kinase) pathways. Data from different experimental models have largely demonstrated that the mutations that induce life-span extension are associated with an altered activity of the above-listed signaling pathways.

Interestingly, the extension of the life-span upon inhibition of the nutrient sensing signaling pathways, has also been associated to the physiological condition induced by calorie restriction (CR). Actually, CR, which consists of the reduction in the caloric intake without malnutrition, has been reported as a robust intervention to promote life-span elongation and healthy aging in rodents at the beginning of last century, and has been further suggested to have similar effects in humans. CR regimens have been shown to induce metabolic adaptations, such as reduced oxidative stress and improved inflammatory response, that ultimately result in better life- and health-spans. Studies performed on experimental models allowed to attribute the life prolongation effects to the modulation of the IGF-1, TOR, and AMPK signaling pathways, but also to other targets, such as FOXO that stimulates protein synthesis and NfkappaB, which is involved in the inflammatory response.

Nowadays, the search for the effects of long-term lifestyle interventions initiated in early adulthood and carried on throughout the entire life captures much attention, due to the evidence that in some tissues and organs, such as the skeletal muscle, the functional decline can begin in adulthood. This interest has prompted several observational studies to understand the correlation between nutrition and health-span, and the potential of CR regimens and CR mimetics in improving the health-span of aging people. At date, there is also a large number of studies aimed at directly testing CR regimens and CR-mimetics, but there are still some shadows on their efficacy, because the time and the interval of the intervention, the variability among individuals, and other factors can compromise their effectiveness.

The Role of Amyloid-β in Neurodegeneration Inside Cells versus Outside Cells
https://www.fightaging.org/archives/2021/08/the-role-of-amyloid-%ce%b2-in-neurodegeneration-inside-cells-versus-outside-cells/

Aggregates of misfolded amyloid-β outside cells are linked to the development of Alzheimer's disease. The failure of immunotherapies that clear those aggregates to achieve meaningful patient benefits indicates that the original form of the amyloid cascade hypothesis of Alzheimer's disease is not correct, however. It has been suggested of late that the aggregates are important because they represent a depletion of soluble amyloid-β, and thus they are the wrong target. An alternative view, described here, is that the prion-like spread of misfolded amyloid-β inside cells is the important issue, and the external aggregates only contribute to a worsening of that problem, rather than being the primary issue themselves.

An experimental study has revealed that the Alzheimer's protein amyloid-beta accumulates inside nerve cells, and that the misfolded protein may then spread from cell to cell via axons. This happens at an earlier stage than the formation of amyloid-beta plaques in the brain, something that is associated with the progression of Alzheimer's disease. The study in question builds on previous research based on amyloid-beta's prion-like properties. This means that the protein adopts a misfolded form that acts as a template for spreading in the brain, where it accumulates and develops plaques.

"The plaques of amyloid-beta outside the nerve cells have long been a target for treatment of Alzheimer's disease. But as treatments to remove plaque have not helped against dementia, we must develop and investigate other hypotheses in order to find other targets for treatment. Our results indicate that amyloid-beta is highly relevant, but that we must focus on misfolded amyloid-beta inside the nerve cells that arise far earlier than the visible plaques."

"The increased amyloid-beta caused by misfolded amyloid-beta inside cells can bring about a vicious circle of more and more amyloid-beta production. This could explain the enormous amounts of amyloid-beta that accumulate in the brain of Alzheimer's patients. However, our results indicate that many of amyloid-beta's damaging effects may be caused by what is happening within the cells, independent of plaques. This may explain why so many experimental treatments targeting plaques outside the nerve cells have failed and that we should focus our attention inwards."

The Age-Related Decline of Mitophagy as a Contributing Cause of Stem Cell Dysfunction
https://www.fightaging.org/archives/2021/08/the-age-related-decline-of-mitophagy-as-a-contributing-cause-of-stem-cell-dysfunction/

Stem cells support the maintenance of tissue by delivering a regular supply of daughter somatic cells to replace losses. Different tissues turn over at different rates, but the contribution of stem cells is vital. Stem cell function declines with age, however, and a slow spiral into frailty and organ failure follows as a consequence. In the most studied populations, this loss of stem cell function is largely a matter of declining activity in response to the age-damaged environment. Put into a youthful environment, stem cells from old tissues can still perform well.

Researchers here draw a line between declining mitophagy and declining stem cell function. Mitophagy is the specialized form of autophagy that removes damaged mitochondria in cells. Mitophagy falters in cells in old tissue due to a range of complicated issues that appear quite distant from the root causes of aging. Necessary proteins are produced in too low an amount, mitochondrial dynamics change, and the component parts of the autophagic system all suffer their own similar problems. Dysfunctional mitophagy leads to dysfunctional mitochondria, and that in turn has a negative impact on stem cell activity.

Mitophagy is a specific autophagic phenomenon in which damaged or redundant mitochondria are selectively cleared by autophagic lysosomes. A decrease in mitophagy can accelerate the aging process. Mitophagy is related to health and longevity and is the key to protecting stem cells from metabolic stress damage. Mitophagy decreases the metabolic level of stem cells by clearing active mitochondria, so mitophagy is becoming increasingly necessary to maintain the regenerative capacity of old stem cells.

Stem cell senescence is the core problem of tissue aging, and tissue aging occurs not only in stem cells but also in transport amplifying cell chambers and the stem cell environment. The loss of the autophagic ability of stem cells can cause the accumulation of mitochondria and the activation of the metabolic state as well as damage the self-renewal ability and regeneration potential of stem cells. However, the claim remains controversial.

Mitophagy is an important survival strategy against nutrient deficiency and starvation, and mitochondrial function and integrity may affect the viability, proliferation, and differentiation potential, and longevity of normal stem cells. Mitophagy can affect the health and longevity of the human body, so the number of studies in this field has increased, but the mechanism by which mitophagy participates in stem cell development is still not fully understood.

Signs of Endothelial Inflammation in Human Neurodegeneration
https://www.fightaging.org/archives/2021/08/signs-of-endothelial-inflammation-in-human-neurodegeneration/

Researchers here provide evidence from human blood samples that supports a role for vascular inflammation in age-related neurodegeneration. It is becoming clear that a great deal of tissue-specific information can be harvested from extracellular vesicles present in the bloodstream, if their contents were only better mapped and understood. The research community is still quite early in the process of establishing the necessary knowledge, but proof of concept demonstrations such as the study noted here are now emerging on a regular basis.

Cerebrovascular disease and the associated blood-brain barrier (BBB) dysfunction are intimately associated with immune activation and among the most common age-associated, inflammation-mediated, degenerative brain changes. Vascular pathways are emerging as an important contributor to neurodegenerative disorders. Importantly, immuno-vascular dysregulation can cause pathology in early disease states, prior to frank brain degeneration and clinical manifestations such as mild cognitive impairment. More recently, molecular pathways are emerging to suggest a feed-forward degenerative-inflammatory phenomenon between endothelial cells, innate immune activation, and degenerative myelin debris. Therefore, identification of molecular biomarkers of immuno-vascular disease in preclinical states has important therapeutic implications for extension of health span, treatment of vascular cognitive impairment.

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70-82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition, and neuroimaging were calculated via regression modelling.

EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated a significant association with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components.

These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

Osteopontin in Blood Samples as a Biomarker of Aging
https://www.fightaging.org/archives/2021/08/osteopontin-in-blood-samples-as-a-biomarker-of-aging/

Much of this paper is taken up with a consideration of osteopontin in macular degeneration, but the authors also note that ostopontin levels in blood plasma are higher in older individuals. This may be connected to increased production in the vasculature, associated with rising levels of chronic inflammation in later life. Past work has also shown that osteopontin levels decline in bone marrow tissue with age, and that this is connected to the dysfunction of the hematopoietic system responsible for generating immune cells. Nothing is simple in the biochemistry of aging.

A common clinical phenotype of several neurodegenerative and systemic disorders including Alzheimer's disease and atherosclerosis is the abnormal accumulation of extracellular material, which interferes with routine cellular functions. Similarly, patients with age-related macular degeneration (AMD), the leading cause of vision loss among the aged population, present with extracellular lipid- and protein-filled basal deposits in the back of the eye. While the exact mechanism of growth and formation of these deposits is poorly understood, much has been learned from investigating their composition, providing critical insights into AMD pathogenesis, prevention, and therapeutics.

We identified human osteopontin (OPN), a phosphoprotein expressed in a variety of tissues in the body, as a newly discovered component of basal deposits in AMD patients, with a distinctive punctate staining pattern. OPN expression within these lesions, which are associated with AMD disease progression, were found to co-localize with abnormal calcium deposition. Mechanistically, we found that retinal pigment epithelial cells, cells vulnerable in AMD, will secrete OPN into the extracellular space, under oxidative stress conditions, supporting OPN biosynthesis locally within the outer retina.

Finally, we report that OPN levels in plasma of aged (non-AMD) human donors were significantly higher than levels in young (non-AMD) donors, but were not significantly different from donors with the different clinical subtypes of AMD. Collectively, our study defines the expression pattern of OPN as a function of disease, and its local expression as a potential histopathologic biomarker of AMD.

A Mechanism by which Amyloid-β Can Cause Degeneration of Synapses
https://www.fightaging.org/archives/2021/08/a-mechanism-by-which-amyloid-%ce%b2-can-cause-degeneration-of-synapses/

Misfolding and aggregation of amyloid-β in the brain is thought to be the initial cause of mild cognitive impairment that leads into Alzheimer's disease. In recent years, this hypothesis has been challenged as clearance of aggregates via immunotherapy has failed to produce improvements in patient outcomes. This may be because the extracellular aggregates are a side-effect and the real harms conducted by amyloid-β occur elsewhere, inside cells. Or it may be that amyloid-β aggregation is a side effect, and other mechanisms such as chronic inflammation and chronic infection are the real drivers of Alzheimer's disease. Nonetheless, mechanistic evidence continues to link amyloid-β with pathology, such as the degeneration of synapses.

In brain disorders such as Alzheimer's, synaptic connections, which hold our precious memories, are known to break down too early and disappear. This synapse degeneration is thought to start long before the loss of memory and accelerate as diseases progress. The causes of synapse degeneration in neurodegenerative disorders has not been well understood, mainly because scientists have not yet unraveled the key mechanisms that normally hold together these tiny structures. Researchers have now identified the main components driving amyloid beta-associated synapse degeneration. Amyloid beta are peptides of 36-43 amino acids derived from the amyloid precursor protein (APP) and are the main component of amyloid plaques found in the brains of people with Alzheimer's disease.

Glutamatergic synapses are highly polarized structures with a presynaptic part from one nerve cell and a postsynaptic part from another. This type of polarity ensures the proper direction of information flow. Researchers had previously found that during brain development the highly polarized synaptic structures are assembled by components of the planar cell polarity (PCP) pathway: a powerful signaling pathway that polarizes cell-cell junctions along the tissue plane. Using super resolution microscopy, the researchers detected the precise location of these same PCP signaling components, called Celsr3, Frizzled3, and Vangl2, in the glutamatergic synapses in the adult brain. They then found that removing these components, essential for the initial assembly of synapses from adult neurons, can dramatically alter the number of synapses. These surprising discoveries suggest that the overall synapse number in a normal brain is maintained by a fine balance between Celsr3 (which stabilizes synapse) and Vangl2 (which disassembles synapses).

Curious about whether these components are involved in synapse degeneration, reserachers tested whether amyloid beta, a key driver of synapse loss in Alzheimer's disease, affects the function or interaction of these proteins. In a series of experiments, they showed that amyloid beta oligomers bind to Celsr3 and allow Vangl2 to more effectively disassemble synapses, likely by weakening the interactions between Celsr3 and Frizzled3. Ryk, a regulator of the PCP pathway that interacts with Frizzled3 and Vangl2, is also found present in the adult synapses and functions in the same way as Vangl2 to mediate synapse disassembly. Blocking Ryk using function-blocking antibodies can protect synapses from amyloid beta-induced degeneration.

The researchers then used 5XFAD mice, a well-known mouse model of amyloid beta pathology. This transgenic mouse carries five human mutations that cause Alzheimer's disease and therefore shows severe symptoms of synapse degeneration and cognitive function loss. They found that removing Ryk by gene knockout from adult neurons protected synapses and preserved cognitive function of 5XFAD mice. Infusion of the function blocking the Ryk antibody also protected synapses and preserved cognitive function in 5XFAD mice, suggesting the Ryk antibody is a potential therapeutic agent.

A Meta-Analysis of the Ability of Aerobic Exercise to Improve Memory and Executive Function
https://www.fightaging.org/archives/2021/08/a-meta-analysis-of-the-ability-of-aerobic-exercise-to-improve-memory-and-executive-function/

Near everyone in the wealthier parts of the world should undertake more physical activity than is presently the case. Too little exercise is harmful. That these populations are largely sedentary makes exercise look like a good intervention, one that improves long-term health considerably. Really, however, that exercise what is needed to bring human health up to par from its present low ebb. We evolved in an environment that required a great deal of physical activity, and many of our critical systems of regulation, maintenance, and stress response are tied to signals that are induced by physical activity. As a result, we corrode into age-related degeneration that much more rapidly in the absence of frequent, sustained exertion.

Aging is the biggest risk factor for cognitive impairment and dementia. Aerobic physical activity may improve cognitive functioning, thus delaying aging-related cognitive decline. The purpose of this review was to examine the effect of aerobic physical activity on memory and executive function in sedentary adults with no known cognitive impairment.

Databases were systematically searched for peer-reviewed articles. Randomized controlled trials of sedentary adults, aged 50 and older, that compared an aerobic physical activity intervention to either no treatment or alternative active comparator and reported outcome measures of memory and/or executive function were included. A random effects meta-analysis was performed to examine the separate effect sizes for memory and executive function.

Nine studies met inclusion criteria and contributed either memory and/or executive function effect sizes (n = 547). Results from the random effects meta-analysis suggested, by post-intervention, a large effect size for the aerobic physical activity interventions on memory and a small effect on executive function. Aerobic physical activity may improve memory and executive function in sedentary adults without cognitive impairment. Policymakers and providers should promote aerobic physical activity in this population, and further research should investigate the most effective ways to promote aerobic physical activity in mid-life to older adults.