Fight Aging!

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Contents

• Lifespan.io Succeeds in Crowdfunding a 200 Person Rapamycin Study
• A Systems Biology Approach to Manipulating the Biochemistry of Senescent Cells
• Only Limited Further Gains in Human Longevity are Likely from Improvement in Environmental Factors
• The Forever Healthy Foundation Knowledge Base on Dasatinib and Quercetin as a Senolytic Therapy
• Is There Really a Solid Correlation Between Periodontitis and Risk of Neurogenerative Disease?
• A Structured Exercise Program Reduces Circulating Biomarkers of Cellular Senescence in Older People
• Senolytic Therapy Alleviates Temporomandibular Joint Degeneration in Old Mice
• Towards More Rigor in the Use of Fasting as a Therapy
• Chronic Inflammation is the Major Cause of Pituitary Gland Aging in Mice
• Provoking Innate Immune Clearance of Protein Aggregates Improves Cognition in a Squirrel Monkey Model of Alzheimer's Disease
• Autologous Cell Therapy Improves Outcomes in Heart Failure Patients
• Long Lived Mammals Exhibit Lower Plasma Methionine Levels
• Acid Ceramidase as a Potential Target for Future Senolytics
• Blood Biomarkers Associated with Atherosclerosis and Mortality
• The Role of Aging Macrophages in Skin Inflammation

Lifespan.io Succeeds in Crowdfunding a 200 Person Rapamycin Study
https://www.fightaging.org/archives/2021/06/lifespan-io-succeeds-in-crowdfunding-a-200-person-rapamycin-study/

It is possible in principle to organize low-cost human trials capable of providing potentially interesting data; much of the cost of formal clinical trials is unrelated to the essentials. The Lifespan.io staff and volunteers have demonstrated this point by successfully raising the modest amount needed to run a 200 person study of the impact of rapamycin use on aging-related biomarkers of health. Rapamycin inhibits mTOR, both the mTORC1 and mTORC2 protein complexes, which have different effects on metabolism. mTOR signaling is involved in the beneficial response to calorie restriction and upregulation of the cellular maintenance process of autophagy, and its inhibition extends healthy longevity in short-lived species such as mice.

The immunosuppressive effects of rapamycin, and a consensus that mTORC2 inhibition is probably undesirable, have led the research community to focus on building specific inhibitors of mTORC1, which are at various stages of clinical development. The the benefits to be obtained from the use of mTOR inhibitors are likely modest, less than those resulting from the actual practice of calorie restriction, but it is certainly the case that more human data is better than less human data. Further, the Lifespan.io study provides a good blueprint for later organizers who may wish to conduct low cost trials for more meaningful interventions, such as the established senolytic combination of dasatinib and quercetin.

PEARL Is Funded, Rapamycin Longevity Clinical Trials Begin

Today is a doubly important day: it marks the final day of the PEARL campaign and it is a celebration of another victory for the life extension community. PEARL smashed its initial fundraising goal and sailed through its two stretch goals, raising just under 183k thanks to the generous support of the community. The Participatory Evaluation (of) Aging (with) Rapamycin (for) Longevity Study, or PEARL, will launch the first large-scale placebo-controlled clinical trial to determine the effects of rapamycin on human aging. The principal investigator is Dr. James P. Watson based at UCLA.

Pearl: Participatory Evaluation of Aging with Rapamycin for Longevity

The PEARL trial will follow up to 200 participants over 12 months testing four different rapamycin dosing regimens. It will be double-blind, randomized, placebo-controlled and registered with clinicaltrials.gov. The principal investigator is Dr. James P Watson at UCLA, who was also a principle investigator for the famous TRIIM trial. To ensure safety the participants' blood will be regularly monitored and side effects noted.

A battery of tests and measurements will be taken, both after 6 and 12 months. These will include autonomic health tests, blood tests, body composition tests, fecal microbiome testing, immune and inflammation health tests, methylation age clock testing, and skeletal muscle tests. With your help we will find out if and how well rapamycin works to combat human aging. And, armed with a positive result, we will finally be able to help slow down onset of age related damage for you and those who you love and care about.

A Systems Biology Approach to Manipulating the Biochemistry of Senescent Cells
https://www.fightaging.org/archives/2021/06/a-systems-biology-approach-to-manipulating-the-biochemistry-of-senescent-cells/

Cells become senescent in response to reaching the Hayflick limit on replication, or to potentially cancerous mutations, or a toxic environment and consequent cell damage, or signaling from other senescent cells. Senescence is nominally an irreversible state. Replication halts and the cell begins secreting pro-inflammatory signals to attract the attention of the immune system. Senescent cells are normally removed via programmed cell death or the actions of cytotoxic immune cells. With age the rate of creation increases and the rate of removal falls, however, leading to a growing number of senescent cells throughout the body. The signaling of that growing number of senescent cells in aged tissues causes chronic inflammation and disrupts tissue maintenance, leading to age-related disease.

What to do about this? Much of the focus of the research community is on senolytic approaches that force senescent cells into apoptosis and self-destruction, or that provoke the immune system into more efficient clearance of senescent cells. These therapies have achieved impressive results in mice, reversing age-related disease and many measures of aging. Some researchers are interested in the reversal of senescence, however: reprogramming cells in ways that overcome the regulatory processes that normally ensure continuation of the senescent state.

Is reversal of senescence a good idea? It seems likely that at least some senescent cells are senescent for a good reason. That they are damaged, and in some cases that damage is potentially cancerous. Reversing senescence may well produce short term gains that are similar to those of senolytic therapies, since in either case the harmful signaling produced by senescent cells is removed. But a significantly raised risk of cancer may be the cost of that approach.

Systems biology for reverse aging

Although partial reprogramming proved that senescent cells can be reverted, early termination of this reprogramming process is known to cause epigenetic dysregulation, resulting in dedifferentiated dysplastic cells such as renal cancer. Therefore, a novel therapeutic strategy without such critical limitations is highly needed. Cellular senescence is caused by complex interactions among biomolecules that govern cell cycle, DNA damage response, energy metabolism, and cytokine secretion. Recent studies showed that cellular senescence, previously considered as an irreversible biological phenomenon, can be reversed, but due to the nature of such complex interactions governing cellular senescence, the mechanism by which cellular senescence can be reversed has not been revealed.

Researchers reconstructed an ensemble of 5000 Boolean network models that can represent senescence, quiescence, and proliferation phenotypes by integrating information from the literature, network databases and phosphoprotein array data of dermal fibroblasts. In their models, cellular senescence is induced by simultaneous activation of DNA damage signal (doxorubicin) and growth signal (IGF-1 plus serum). They identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as the optimal protein target that can safely revert senescence to quiescence while avoiding uncontrolled proliferation, through extensive computer simulation analysis of the ensemble model. PDK1 forms a positive feedback structure along with AKT, IKBKB, and PTEN, that simultaneously control both nuclear factor κB, which controls cytokine secretion, and mTOR, which regulates cell growth.

In order to validate the simulation results, researchers conducted in vitro experiments and confirmed that when PDK1 was inhibited, various markers of cellular senescence are returned to normal and proliferation potential is restored. From wound healing assays and 3D reconstructed skin tissue experiments, they also reaffirmed that the reverted cells are able to respond appropriately to external stimuli. In particular, by observing dermal fibroblast within dermis along with keratinocyte within epidermis, 3D reconstructed skin tissue experiments verified that PDK1 inhibition promotes epidermal renewal and restores skin thickness, resulting in reversal of age-related skin degeneration.

Only Limited Further Gains in Human Longevity are Likely from Improvement in Environmental Factors
https://www.fightaging.org/archives/2021/06/only-limited-further-gains-in-human-longevity-are-likely-from-improvement-in-environmental-factors/

Today's open access paper offers one of a number of different perspectives on the present consensus regarding the causes of individual variance in life expectancy, of differences in species life span, and of changes in human life expectancy over time. Human life expectancy has increased greatly in the modern era, but this is largely due to improved control over infectious disease and other environmental factors that can cause early mortality and long-term health risks. Similarly, individual variance in life span near entirely arises from lifestyle choice and environmental factors. There is a component arising from slowed aging, but this has been an incidental side-effect of improved technologies, medical and otherwise.

The authors of the paper here suggest that life expectancy and mortality data shows that further improvements in the known environmental factors that impact health are unlikely to yield meaningful gains in human life expectancy. The lion's share of possible gains are already claimed, thanks to control of infectious disease and other outcomes of modern technologies. New approaches to age-related degeneration are needed, development programs and therapies that deliberately target the causative mechanisms of aging. Historical data says little about what human life expectancy will look like in the era of widespread use of senolytic treatments and other rejuvenation therapies now under development.

The long lives of primates and the 'invariant rate of ageing' hypothesis

The maximum human life expectancy has increased since the mid-1800s by ~3 months per year. These gains have resulted from shifting the majority of deaths from early to later and later ages, with no evidence of slowing the rate at which mortality increases with age (i.e. the 'rate of ageing'). Further substantial extensions of human longevity will depend on whether it is possible to slow the rate of ageing or otherwise reduce late life mortality. Consequently, the nature of biological constraints on ageing is a central problem in the health sciences and, because of its implications for demographic patterns, is also of long-standing interest in ecology and evolutionary biology.

Across species, rates of ageing are strongly correlated with other aspects of the life history-pre-adult mortality, age at first reproduction, birth rate, metabolic rate and generation time - as well as with morphological traits such as body size and growth rate. These correlations suggest that ageing evolves in concert with a suite of other traits, which may produce constraints on the rate of ageing within species. Indeed, researchers have long hypothesised that the rate of ageing is relatively fixed within species, not only in humans but also other animals.

This 'invariant rate of ageing' hypothesis has received mixed support. Understanding the nature and extent of biological constraints on the rate of ageing and other aspects of age-specific mortality patterns is critical for identifying possible targets of intervention to extend human lifespans, and for understanding the evolutionary forces that have shaped lifespans within and across species. Although no consensus has been reached about the invariant rate of ageing hypothesis, further evidence that biological constraints may shape human ageing comes from the remarkably consistent relationship between life expectancy at birth and lifespan equality in a diverse set of human populations. While life expectancy at birth (a measure of the 'pace' of mortality) describes the average lifespan in a population, lifespan equality (a measure of the 'shape' of mortality) describes the spread in the distribution of ages at death in a population.

To better understand biological constraints on ageing, here we answer two questions. First, is the highly regular linear relationship between life expectancy and lifespan equality in humans also evident in other primates? Second, if so, do biological constraints on ageing underlie this highly regular relationship? We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed.

Can we humans slow our own rate of ageing? Our findings support the idea that, in historical population when life expectancies were low, mortality improvements for infants, and in age-independent mortality, were the central contributors to the decades-long trend towards longer human life expectancies and greater lifespan equality. These improvements were largely the result of environmental influences including social, economic, and public health advances. Since the middle of the 20th century, however, declines in the baseline level of adult mortality have very likely played an increasingly important role in industrialised societies. As we show here, improvements in the environment are unlikely to translate into a substantial reduction in the rate of ageing, or in the dramatic increase in lifespan that would result from such a change. It remains to be seen if future advances in medicine can overcome the biological constraints that we have identified here, and achieve what evolution has not.

The Forever Healthy Foundation Knowledge Base on Dasatinib and Quercetin as a Senolytic Therapy
https://www.fightaging.org/archives/2021/06/the-forever-healthy-foundation-knowledge-base-on-dasatinib-and-quercetin-as-a-senolytic-therapy/

The Forever Healthy Foundation has been building a database of materials covering presently available options for the treatment of aging, all of which have little available data in comparison to more established areas of medicine. The bias in these materials is towards a very conservative viewpoint, appropriate for physicians, so you will see little to no enthusiasm for forging ahead with use, as the self-experimenters in the longevity community are presently doing. Nonetheless, this provides a convenient repository of information, pulling together references to all of the animal and human data available for the topics under discussion.

The latest article covers the senolytic combination of dasatinib and quercetin, currently in human trials, and with more and better data to back it up than most other approaches. The effects in mice are eye-opening in comparison to anything else yet tried in the field of rejuvenation; quite rapid reversal of many age-related diseases and measures of age-related degeneration. Dasatinib is a chemotherapeutic, and when used continuously produces the usual range of unpleasant, toxic outcomes. When used only very intermittently, as a senolytic, the situation is very different. Still, as pointed out here, there is little data in humans, if one is to be conservative.

Dasatinib and Quercetin Senolytic Therapy

Clinical data on the possible benefits and risks of using dasatinib and quercetin (D+Q) as senolytics is extremely limited. Published results exist from 3 human trials, two in diseased populations and one in healthy subjects. A total of only 8 benefits were documented in these clinical studies. Of the 8 benefits, 5 were actually various measurements of markers of senescence or the SASP, hypothesized to translate to clinically beneficial effects. Only 3 benefits had any direct clinical relevance and they were of low magnitude. Based on the current state of evidence, the beneficial effects of D+Q seem to be extremely limited in humans.

Several more benefits that encompass many organ systems have been reported in preclinical studies. However, the amount of relevant preclinical research is also limited. We identified only 31 preclinical trials related to D+Q as senolytics and the majority of reported benefits occurred exclusively in diseased animals. Only 13 trials included a group of "healthy" animals that were treated with D+Q. Of those 13 trials, only 6 reported a positive effect of D+Q senolytic treatment on aged, otherwise healthy animals as compared to controls.

The main benefits seen in clinical and preclinical trials of D+Q senolytic therapy are: (a) decreased markers of senescent cells in various tissues (clinical and preclinical); (b) increased health span and lifespan (preclinical); (c) improved cognition and cortical blood flow (preclinical); (d) decreased amounts of liver fat (preclinical); (e) improved vasomotor/endothelial function (preclinical); (e) decreased intimal plaque calcification (preclinical). The main risks that have appeared in clinical trials are mostly due to dasatinib. In the two high quality, open-label human pilot senolytic trials there was only one serious adverse event reported (bacterial multifocal pneumonia and pulmonary edema superimposed on the idiopathic pulmonary fibrosis that was the subject of the trial) and no subjects required drug discontinuation.

The 3 clinical trials published to date have all used different protocols (doses, frequency, duration, and repetition). There is no consensus on the optimal treatment protocol. Unfortunately, as of today, there is no single test that is completely sensitive or specific for senescent cells. Generally, a combination of assays is needed to estimate the senescent cell burden in tissue samples. It is unknown if senescent cell abundance in biopsies of skin, adipose tissue, or other tissues, cheek swabs, cells in blood reliably reflect senescent cell abundance overall. Similarly, whether levels of SASP factors or senescence-associated microRNAs in plasma or blood cells reflect senescent cell burden is not clear.

Therefore, until there are more published results showing benefits in humans, a clearer picture of the senolytic-use specific risk profile, and a consensus on the treatment protocol, we will avoid the use of D+Q senolytic therapy.

Is There Really a Solid Correlation Between Periodontitis and Risk of Neurogenerative Disease?
https://www.fightaging.org/archives/2021/06/is-there-really-a-solid-correlation-between-periodontitis-and-risk-of-neurogenerative-disease/

A number of papers in recent years have suggested there to be a link between gum disease (periodontitis) and neurodegeneration. Similarly to the correlation with heart disease, it is thought that the underlying mechanism is raised chronic inflammation deriving from toxins released into the bloodstream by the bacteria that cause gum disease. Some epidemiological data suggests that the effect size is modest at best, however - a 6% increase in risk in one cohort, for example. So is there in fact a meaningful link between inflammatory gum disease and forms of neurodegeneration that are thought to be driven in large part by the chronic inflammation of aging? The hypothesis seems reasonable, but as today's open access paper notes, the evidence to date is just not that great.

This is often the way of things in research into the contributing mechanisms of age-related diseases. Having gingival bacteria release immune-provoking compounds into the bloodstream sounds like something to be avoided, and one can find plenty of evidence for this mechanism to exist. The bacteria are definitely there in the mouth, the immune response to their presence established in various ways. But is it causing enough harm in comparison to all of the other damage and dysfunction of an aged metabolism to be influential outside the local issue of gum disease?

Perhaps, perhaps not; the epidemiological data as it stands isn't enough for a concrete conclusion when taken collectively. This may be a case of where there is smoke there is fire, and better and larger studies would produce conclusive outcomes, but it is hard to say in advance. Nonetheless, it is near universally agreed that maintaining as low a level of chronic inflammation as possible with advancing age is a good idea.

Is There Any Association Between Neurodegenerative Diseases and Periodontitis? A Systematic Review

Some inflammatory diseases, such as periodontitis, might represent a factor that can contribute to central nervous system (CNS) damage. Periodontitis is a multifactorial chronic inflammatory disease that affects the supporting tissues around the teeth, triggered by dysbiotic biofilms that can lead to systemic inflammation. Periodontal disease is one of the most frequent causes of tooth loss, and is highly prevalent in adults affecting about 20-50% of the global population. It can lead to a systemic inflammatory state through mechanisms that include the spread of pro-inflammatory cytokines and/or bacteria located in the oral cavity. Persistent systemic inflammation/infection can cause neuroinflammation in the brain. Considering this possible interaction, the present study aims to systematically review the evidence supporting the association between the presence of some neurodegenerative disease and periodontitis.

From 534 articles found in this systemic review, 12 were included, of which eight were case-control, three were cross-sectional, and one was a cohort, giving a total of 3,460 participants. All studies presented a low risk of bias and reported an association between neurodegenerative disease and periodontitis. The articles showed that the groups with the two concomitant diseases had higher inflammatory markers levels, IgG levels of periodontal bacteria, and/or clinical parameters of periodontitis compared with the isolated conditions. However, the heterogeneity of the studies taken together hindered the accuracy of the evidence and also made impossible the merging of data. Also, it should be highlighted that no cohort study was retrieved regarding the association between periodontal disease and neurodegenerative diseases; therefore, causality cannot be claimed.

Although all the included studies in this review reported an association between neurodegenerative diseases and periodontitis, the level of evidence was classified to be very low, which suggests a cautious interpretation of the results.

A Structured Exercise Program Reduces Circulating Biomarkers of Cellular Senescence in Older People
https://www.fightaging.org/archives/2021/06/a-structured-exercise-program-reduces-circulating-biomarkers-of-cellular-senescence-in-older-people/

Researchers here suggest that exercise interventions affect the turnover rate of senescent cells in older people, mostly likely by both reducing the pace at which cells become senescent, and improving the pace of clearance by the immune system. The size of the effect is modest, as one might expect, given that exercise cannot hold a candle to the benefits produced by senolytic drugs when it comes to reversing measures of aging in mice. This and other recent evidence increasingly suggests that individual senescent cells do not linger for very long in the body in later life. The observed accumulation with age is instead the outcome of a progressively growing imbalance between mechanisms of creation and mechanisms of destruction.

Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined.

Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention.

Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.

Senolytic Therapy Alleviates Temporomandibular Joint Degeneration in Old Mice
https://www.fightaging.org/archives/2021/06/senolytic-therapy-alleviates-temporomandibular-joint-degeneration-in-old-mice/

Senescent cell accumulation appears to be a major player in the pathology of most of the joint-related issues that occur in older individuals. Senescent cells secrete signals that provoke a state of chronic inflammation, alter nearby cell behavior, and disrupt tissue structure and maintenance. Clearance of these cells reverses numerous age-related conditions and measures of aging in mice. Hence the advent of senolytic therapies that selectively destroy senescent cells is a much anticipated development in medicine. Indeed, the first such therapies are pre-existing drugs, such as the dasatinib and quercetin combination, are already in human trials, producing promising initial data, and in principle available to any individual who can convince a physician to write an off-label prescription.

Aging is one of the major risk factors for degenerative joint disorders, including those involving the temporomandibular joint (TMJ). TMJ degeneration occurs primarily in the population over 65, significantly increasing the risk of joint discomfort, restricted joint mobility, and reduced quality of life. Unfortunately, there is currently no effective mechanism-based treatment available in the clinic to alleviate TMJ degeneration with aging.

We now demonstrate that intermittent administration of the senolytic combination of dasatinib and quercetin, which can selectively clear senescent cells, preserved mandibular condylar cartilage thickness, improved subchondral bone volume and turnover, and reduced Osteoarthritis Research Society International (OARSI) histopathological score in both 23- to 24-month-old male and female mice. Senolytics had little effect on 4 months old young mice, indicating age-specific benefits.

Our study provides proof-of-concept evidence that age-related TMJ degeneration can be alleviated by pharmaceutical intervention targeting cellular senescence. Since the senolytics used in this study have been proven relatively safe in recent human studies, our findings may help justify future clinical trials addressing TMJ degeneration in old age.

Towards More Rigor in the Use of Fasting as a Therapy
https://www.fightaging.org/archives/2021/06/towards-more-rigor-in-the-use-of-fasting-as-a-therapy/

Fasting produces benefits to health that are meaningful in comparison to the cost of this intervention - it is free, and the health benefits are reliable and repeatable. When it comes to improved metabolism and long-term health benefits, no medical technology is yet established to do better than the practice of intermittent fasting or calorie restriction in people without severe medical conditions. Senolytic therapies should hopefully greatly improve on this performance in older individuals, but that data has yet to emerge. As researchers point out here, fasting is not usually rigorously applied in medical practice. There are groups working on approaches, for example the fasting mimicking diet that is intended to set a standard for how to apply reduced calorie intake as a therapy. But more generally, much work is left to accomplish if fasting is to be integrated into medical practice in the same way as pharmacological approaches have been.

Recently, fasting has become one of the most compelling topics of the Nutrition Era. In the last five years, interest has passed from the Mediterranean to the Ketogenic Era, including the concept of caloric restriction and 'only water' fasting. Recently, research in animal models and humans has highlighted the potential health-promoting physiological responses to fasting including ketogenesis, hormone modulation, reduced oxidative stress and inflammation, and increased stress resistance, lipolysis, and autophagy. Although the panorama of evidence on fasting and caloric restriction is wide, there is a lack of a correct and safe fasting protocol to guide nutritionists and physicians in its application.

The act of fasting gained an increased focus in the scientific panorama thanks to several pieces of research developed around 30 years ago. The first studies referred to minor organisms and not directly to humans, because fasting and caloric restriction were considered tough interventions, combined with health risks if not adequately structured. Initially, studies on yeasts and murine models brought remarkably interesting results, later to be replicated in humans.

Some people, to be committed to their health, try adopting new habits as nutritional styles change. Nowadays, people are motivated by information from various sources: media, social networks, doctors, gyms, health coaches, and, simply, word of mouth and rumor. The accumulated information is not in line with scientific discoveries and safety protocols. Mere abstinence from food cannot result in efficacy if it is not well contextualized within a structured nutritional intervention. Fasting improves blood biomarkers for metabolic health, stress resistance, and suppresses inflammation. For example, most Westerners emulate their idols, picking up a fasting model that is supposed to help with losing and sustaining weight, keeping mentally sharp, and promoting longevity. Most of the time they do not experience the suggested benefits because of an unbalanced diet.

In the light of the above, the goal of our paper is to examine the context in which fasting could be practiced, and the most important discoveries in fasting used in pathological conditions such as chronic degenerative diseases. Moreover, it aims to offer to clinical experts in nutrition a specific guide to be consulted and personalized for each patient.

Chronic Inflammation is the Major Cause of Pituitary Gland Aging in Mice
https://www.fightaging.org/archives/2021/06/chronic-inflammation-is-the-major-cause-of-pituitary-gland-aging-in-mice/

The pituitary gland regulates numerous processes in the body via endocrine signaling. Of particular interest is the relationship between the pituitary gland and the thymus, which appear to influence one another via still poorly understood exchanges of signals. The thymus is of great importance to immune function, but atrophies with age. There is some data to suggest that provoking greater pituary gland activity can reverse that process, at least in mice. Researchers here provide evidence for the age related degeneration of the pituitary gland and its function in the body to be largely the consequence of rising systemic inflammation characteristic of aging. Interestingly, similar conclusions have been drawn for the aging of the thymus.

The pituitary gland is a small, globular gland located underneath the brain that plays a major role in the hormonal system. Due to the central role played by the pituitary, its ageing may contribute to the reduction of hormonal processes and hormone levels in our body - as is the case with menopause, for instance. A new study provides significant insight into the stem cells in the ageing pituitary gland. In 2012, researchers showed that a prompt reaction of stem cells to injury in the gland leads to repair of the tissue, even in adult animals. "As a result of this new study, we now know that stem cells in the pituitary do not lose this regenerative capacity when the organism ages. In fact, the stem cells are only unable to do their job because, over time, the pituitary becomes an 'inflammatory environment' as a result of the chronic inflammation. But as soon as the stem cells are taken out of this environment, they show the same properties as stem cells from a young pituitary."

This insight opens up a number of potential therapeutic avenues: would it be possible to reactivate the pituitary? This wouldn't just involve slowing down hormonal ageing processes, but also repairing the damage caused by a tumour in the pituitary, for example. The study also suggests another interesting avenue: the use of anti-inflammatory drugs to slow down pituitary ageing or rejuvenate an ageing pituitary. "Several studies have shown that anti-inflammatory drugs may have a positive impact on some ageing organs. No research has yet been performed on this effect in relation to the pituitary."

"Mice have a much greater regeneration capacity than humans. They can repair damaged teeth, for instance, while humans have lost this ability over the course of their evolution. Regardless, there are plenty of signs suggesting that pituitary processes in mice and humans are similar, and we have recent evidence to hand that gene expression in the pituitaries of humans and mice is very similar. As such, it is highly likely that the insights we gained in mice will equally apply to humans."

Provoking Innate Immune Clearance of Protein Aggregates Improves Cognition in a Squirrel Monkey Model of Alzheimer's Disease
https://www.fightaging.org/archives/2021/06/provoking-innate-immune-clearance-of-protein-aggregates-improves-cognition-in-a-squirrel-monkey-model-of-alzheimers-disease/

A novel pulsed approach to immunotherapy targeting Alzheimer's disease has been shown to reduce both amyloid-β and tau aggregates in old squirrel monkeys, as well as improve cognitive function. This species offers a potentially less problematic and artificial animal model for the condition, in that aged squirrel monkeys naturally develop amyloid-β aggregates, unlike mice which must be engineered into exhibiting specific features of Alzheimer's pathology. Thus it is hoped that cognitive improvements following therapy in this species will be more likely to also occur in human patients.

Researchers have demonstrated that elderly monkeys had up to 59 percent fewer plaque deposits in their brains after treatment with CpG oligodeoxynucleotides (CpG ODN), compared with untreated animals. These amyloid beta plaques are protein fragments that clump together and clog the junctions between neurons. Brains of treated animals also had a drop in levels of toxic tau. This nerve fiber protein can destroy neighboring tissue when disease-related changes to its chemical structure cause it to catch on other cells.

The investigators say the treatment led to cognitive benefits as well. When presented with a series of puzzles, elderly monkeys given the drug performed similarly to young adult animals and much better than those in their age group that had remained untreated. The treated monkeys also learned new puzzle-solving skills faster than their untreated peers. According to researchers, past treatment efforts targeting the immune system failed because the drugs overstimulated the system, causing dangerous levels of inflammation, which can kill brain cells. "Our new treatment avoids the pitfalls of earlier attempts because it is delivered in cycles, giving the immune system a chance to rest between doses."

A growing body of evidence has implicated the immune system, the set of cells and proteins that defend the body from invading bacteria and viruses, as a contributor to Alzheimer's disease. A subset of immune cells, those within the innate immune system, swallow and clear away debris and toxins from bodily tissues along with invading microbes. Studies have shown that these immune custodians become sluggish as a person ages and fail to clear toxins that cause neurodegeneration.

The new investigation is the first to target the innate immune system with a potential therapy for the disorder in monkeys. The CpG ODN drugs are part of a class of innate immune regulators that quicken these worn out immune custodians. The research team is also the first to use the "pulsing" drug administration technique to avoid excess inflammation, the immune-driven responses like swelling and pain that result from the homing in by immune cells on sites of injury or infection. While necessary to immune defenses and healing, too much inflammation contributes to many disease mechanisms.

Autologous Cell Therapy Improves Outcomes in Heart Failure Patients
https://www.fightaging.org/archives/2021/06/autologous-cell-therapy-improves-outcomes-in-heart-failure-patients/

Numerous forms of cell therapy have been proposed and tested for the treatment of heart failure over the years, from the earliest stem cell therapies to the broader variety of cell types and increasing technical sophistication attempted today. The results here seem promising. Much of the challenge of early efforts was the lack of reliability in outcomes. While first generation stem cell therapies fairly reliably reduce inflammation, they have not delivered on the promise of regeneration. Clinical trials are overly costly in the present system of regulation, and could be run at far less expense absent the regulators, but something like passing a clinical trial with a hundred or more patients is an important milestone to demonstrate reliability. The effect size demonstrated here is modest - a ~20% reduction in cardiac events, with none of the desired structural changes in the heart in evidence - but that is a starting point.

A clinical trial has shown for the first time that heart failure treatments using cells derived from the patient's own bone marrow and heart resulted in improved quality of life and reduced major adverse cardiac events for patients after one year. "This is a very important advance in the field of cell therapy and in the management of heart failure. It suggests that a treatment, given only once, can produce long-term beneficial effects on the quality of life and prognosis of these patients. The results pave the way for a larger, Phase 3 trial of cell therapy in heart failure."

CONCERT-HF evaluated the use of two types of cells - autologous mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs) - alone or in combination, in patients with heart failure caused by chronic ischemic cardiomyopathy, a decrease in heart pumping effectiveness due to heart attacks and a lack of blood getting to the heart. Autologous MSCs are derived from the patient's bone marrow and CPCs are from the patient's heart tissue. Both are known as "autologous" cells because they come from the same patient in whom they are returned for the treatment.

In the study, patients treated with CPC cells alone had a significant 22% reduction in major adverse cardiac events, particularly hospitalization. Patients treated with MSC cells alone and with a combination of both types of cells experienced significantly improved quality of life compared with patients who received no treatment. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups.

Long Lived Mammals Exhibit Lower Plasma Methionine Levels
https://www.fightaging.org/archives/2021/06/long-lived-mammals-exhibit-lower-plasma-methionine-levels/

Mechanisms to sense levels of the essential amino acid methionine are one of the more important triggers for the beneficial calorie restriction response in mammals. Since the body doesn't manufacture methionine, it must come from the diet. Either a low calorie diet or a low methionine diet produce broadly similar effects of improved metabolism, health, and longevity, though different in the fine details. Short-lived species, however, have a much larger gain in life span than is the case in longer-lived species. Calorie restriction can make mice live 40% longer, but it certainly doesn't add more than a few years in humans.

Why this is the case, when short-term metabolic responses and benefits appear broadly similar in both short-lived and long-lived mammals, is an open question. In this context, the research here is quite interesting. If background levels of methionine are lower in long-lived species, perhaps the shared trigger mechanisms relating to methionine are less capable of producing sizable effects in long-term health - though again, a detailed understanding of exactly how this happens has yet to be established.

All living organisms use the same 20 amino acids for protein synthesis. Interestingly, the protein compositional content of the sulfur amino acids methionine and cysteine is species-specific and is associated with animal longevity. Thus, long-lived animal species show the lower methionine and cysteine protein content, surely as adaptive response to the low rate of endogenous damage and highly resistant macromolecular components also present in longevous species. Reinforcing these observations, the free tissue methionine content is also lower in diverse long-lived animal species; and the pro-longevity effects of nutritional (methionine restriction, MetR) and pharmacological (metformin) interventions are mediated by changes in methionine metabolism.

In addition to its role in several intracellular processes, methionine is the core of a complex metabolic network which can be divided in three parts: methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Significantly, manipulation of each of these branches affects longevity in diverse experimental animal models. Consequently, available findings point to the metabolism of methionine as a key target to study the molecular adaptive mechanisms underlying differences in animal longevity.

The present study follows a comparative approach to analyse the plasma methionine metabolic profile from 11 mammalian species with a longevity ranging from 3.5 to 120 years. Our findings demonstrate the existence of a species-specific plasma profile for methionine metabolism associated with longevity characterised by: i) reduced methionine, cystathionine and choline; ii) increased non-polar amino acids; iii) reduced succinate and malate; and iv) increased carnitine. Our results support the existence of plasma longevity features that might respond to an optimised energetic metabolism and intracellular structures found in long-lived species.

Acid Ceramidase as a Potential Target for Future Senolytics
https://www.fightaging.org/archives/2021/06/acid-ceramidase-as-a-potential-target-for-future-senolytics/

The accumulation of senescent cells is an important contributing cause of degenerative aging. This is not a recent discovery, enough was known 20 years ago for the first SENS rejuvenation research proposals to prominently feature removal of senescent cells as an approach to treating aging as a medical condition, but it has only become broadly accepted by the research community over the past decade. There has been a considerable growth of interest in cellular senescence, particularly over the last few years as the first (mixed) human data emerged.

There is a something of a land rush underway in the exploration of the biochemistry of senescent cells at the moment, given that every new discovery might lead to potential means of destroying these cells - or perhaps suppressing their harmful signaling in some way - and thus investment, new startup companies to join the growing longevity industry, and potential profit. It remains to be seen which of the many first generation approaches to the selective destruction of senescent cells will win out in the marketplace of medical development, and meanwhile new discoveries are being made by researchers on a fairly regular basis.

Cellular senescence is linked to chronic age-related diseases including atherosclerosis, diabetes, and neurodegeneration. Compared to proliferating cells, senescent cells express distinct subsets of proteins. In this study, we used cultured human diploid fibroblasts rendered senescent through replicative exhaustion or ionizing radiation to identify proteins differentially expressed during senescence. We identified acid ceramidase (ASAH1), a lysosomal enzyme that cleaves ceramide into sphingosine and fatty acid, as being highly elevated in senescent cells. This increase in ASAH1 levels in senescent cells was associated with a rise in the levels of ASAH1 mRNA and a robust increase in ASAH1 protein stability.

Furthermore, silencing ASAH1 in pre-senescent fibroblasts decreased the levels of senescence proteins p16, p21, and p53, and reduced the activity of the senescence-associated β-galactosidase. Interestingly, depletion of ASAH1 in pre-senescent cells sensitized these cells to the senolytics dasatinib and quercetin (D+Q).

Together, our study indicates that ASAH1 promotes senescence, protects senescent cells, and confers resistance against senolytic drugs. Given that inhibiting ASAH1 sensitizes cells towards senolysis, this enzyme represents an attractive therapeutic target in interventions aimed at eliminating senescent cells.

Blood Biomarkers Associated with Atherosclerosis and Mortality
https://www.fightaging.org/archives/2021/06/blood-biomarkers-associated-with-atherosclerosis-and-mortality/

Researchers here present evidence for leukocyte telomere length and a few other less well explored blood biomarkers to correlate with the progression of atherosclerosis and vascular calcification and later mortality. Calcification of blood vessels and the development of fatty atherosclerotic lesions are two distinct processes, but they tend to progress together, most likely because they are both driven to a sizable degree by the presence of chronic inflammation, and related issues such as burden of senescent cells.

Increased oxidative stress, leukocyte telomere length (LTL) shortening, endothelial dysfunction, and lower insulin-like growth factor (IGF)-1 concentrations reflect key molecular mechanisms of aging. We hypothesized that biomarkers representing these pathways are associated with measures of subclinical atherosclerosis and all-cause mortality.

We evaluated 2,314 Framingham Offspring Study participants (mean age 61 years, 55% women) with available biomarkers of aging: LTL, circulating concentrations of IGF-1, asymmetrical dimethylarginine (ADMA), and urinary F2-Isoprostanes indexed to urinary creatinine. We evaluated the association of each biomarker with coronary artery calcium (CAC) and carotid intima-media thickness (IMT).

In multivariable-adjusted linear regression models, higher ADMA levels were associated with higher CAC values. Additionally, shorter LTL and lower IGF-1 values were associated with higher IMT values. During a median follow-up of 15.5 years, 593 subjects died. In multivariable-adjusted Cox regression models, LTL and IGF-1 values were inversely associated with all-cause mortality. F2-Isoprostanes and ADMA values were positively associated with all-cause mortality.

In conclusion, in our prospective community-based study, aging-related biomarkers were associated with measures of subclinical atherosclerosis cross-sectionally and with all-cause mortality prospectively, supporting the concept that these biomarkers may reflect the aging process in community-dwelling adults.

The Role of Aging Macrophages in Skin Inflammation
https://www.fightaging.org/archives/2021/06/the-role-of-aging-macrophages-in-skin-inflammation/

The immune system is complex and ages in complex ways, pressed by the lifetime burden of infection and rising levels of molecular damage that trigger many of the same innate immune responses as are produced by invading pathogens. The common innate immune cells known as macrophages play many roles in the body: defense against pathogens; destruction of errant cells; assisting in tissue maintenance and regeneration. Macrophages adopt different phenotypes (M1, M2, and others) depending on the task at hand.

The aging of the macrophage population, and also the analogous microglia of the central nervous system, is not as simple a matter as there being too many angry, inflammatory M1 macrophages and too few regenerative, anti-inflammatory M2 macrophages. There is, however, a sizable amount of evidence to suggest that this growing imbalance towards inflammatory macrophage behavior is a major cause of issues in older individuals. The perspective of this review paper on macrophage aging is a narrow one, focused on skin only, but much of the discussion is applicable to other tissues.

The skin is our largest organ. Its aging reflects both intrinsic (or chronological) and extrinsic (such as radiation and pollution exposure) aging processes at the molecular and phenotypic levels. Skin aging is a process accompanied by changes that alter the local microenvironment, such as weakening of the skin barrier and the accumulation of stressed and senescent cells, both of which foster inflammation through the invasion/release of Pathogen-Associated Molecular Patterns and Damage-Associated Molecular Patterns. The consequences of such an altered microenvironment include the promotion of the senescence-associated secretory phenotype (SASP), compromising tissue renewal and function, altered cellular interactions, and chronic low-grade inflammation. This sterile inflammatory state, termed inflammaging, develops in several organs with advanced age and is associated with persistent inflammation that ultimately exhausts the skin's defense system.

Macrophages (Mφ), a group of heterogeneous and plastic cells, play a central role in tissue homeostasis and repair, as well as host defense. In the skin, Mφ can be found in different layers, being classified as recruited Mφ originating from monocytes following a recruitment process started by tissue injury, or as tissue-resident macrophages (TRM), which are derived from both adult and embryonic progenitors. Mφ may acquire different phenotypes in response to various stimuli. In this sense, based on in vitro assays, Mφ have been divided into two groups based on their polarization phenotypes: M1 and M2. Classically activated Mφ are deemed as M1 and constitute catabolic, proinflammatory cells that are involved in antimicrobial host defense. M2, or alternatively activated Mφ, are anabolic cells with anti-inflammatory and tissue repair properties. However, mainly due to recent advances in single-cell RNA sequencing, it is now clear that such a dichotomy does not accurately represent Mφ in vivo but represents the extremes of a wide range of continuous phenotypes which have been reported.

The aging process has a great impact on Mφ, including alterations in Mφ metabolic and immune function, impacting the Mφ capability of clearance and immunosurveillance, constituting an important aspect of immunosenescence. In fact, old Mφ in a mice model were characterized with a senescent, proinflammatory profile, associated with increased oxidative stress, compromised antioxidant defenses, and impaired function. Mφ are considered as gatekeepers of tissue homeostasis and integrity, constituting primary inflammatory cytokine producers, as well as initiators and regulators of inflammation, and representing one of the main cellular players in adaptive immunity exacerbation and exhaustion during aging. In recognition of the age-related alterations on Mφ function and their importance during skin aging, in this review, we will dissect how aging hallmarks may alter the Mφ phenotype and function and connect these plastic cells with skin inflammaging.