Fight Aging!

Is it possible to safely introduce developmental signaling characteristic of the developing embryo and fetus into an aged adult in order to spur greater regeneration of tissues? The past decades of work on embryonic stem cell therapies and induced pluripotent stem cell therapies, and the slow investigation of how most of these therapies produce their benefits via cell signaling, suggest that this goal is in principle possible. Similarly, research into species capable of proficient regeneration, such as salamanders and zebrafish, suggests broad similarities between the biochemistry of organ development and the biochemistry of organ regrowth.

The issue for we mammals has all along been the question of cancer. Would developmental signaling result in an unacceptable cancer risk, either by directly breaking regulatory systems important in tissue maintenance, or by forcing greater cell activity in an environment of age-related damage?

Researchers continue to investigate the mechanisms of stem cell therapies, the contents of pro-regenerative extracellular vesicles and their effects on bystander cells, and partial cell reprogramming in vivo. As this work progresses, numerous potential approaches are arising to the delivery of specific developmental signals. The paper here takes a look at one very narrow slice of this part of the regenerative medicine field, what is know of developmental peptide signals, and particularly thymosin beta-4, that might be exploited to boost adult regeneration in later life.

Utilizing Developmentally Essential Secreted Peptides Such as Thymosin Beta-4 to Remind the Adult Organs of Their Embryonic State - New Directions in Anti-Aging Regenerative Therapies

Reversing age-related alterations of the body is a long-desired goal of humankind. Despite the extravagant premise, the dream of returning to our youth may not be so far-fetched. Nature actually provides an enormous list of molecules, some of which are silenced after birth but could serve as a potential treatment to reverse age, at least at the level of a single yet complicated organ such as the heart. The question remains: can postnatal increase of developmentally relevant proteins and peptides reverse organ ageing or damage in a beneficial way? We believe the answer to this question is yes. In our earlier research, we introduced a naturally secreted small molecule, Thymosin beta-4 (TB4), which is capable of such miracles not only regarding the heart but in the brain and kidneys.

TB4 was first purified from the thymus and binds and alters the cytoskeletal actin filaments by sequestering actin monomers and in doing so, influences actin filament assembly and regulates migration of various cell types such as endothelial cells, myocardial cells, or epicardial progenitors. It equally inhibits cellular death by activating and binding numerous players in the focal adhesion complex, which, eventually, results in the activation of Akt, a proven substrate of ILK with wide-ranging signalling functions that affect growth, survival, and motility. Naturally, all the other mechanisms by which TB4 initiates the increase of cardiac function are still under investigation by a host of scientists worldwide. Undoubtedly, its capability in activating the adult epicardium and its ability to resemble its embryonic function without risking injury suggests grounds for hope that the molecule does achieve the same in other organs.

Reminding adult cells of their highly proliferative state is not without risk, as the applied treatment may easily result in unwanted malignancies. Although TB4 was reported to be a prognostic marker for highly metastatic cancer states and its tumor promo-ting properties were equally demonstrated, its true nature regarding tumorigenesis is controversial. In our hands, the molecule significantly inhibited the progression of pancreatic cancer following systemic administration in mice in vivo. An additional factor supporting this result is that TB4 was equally introduced as a candidate tumor suppressor in male breast cancer and was demonstrated to have a tumor suppressive function in myeloma development by other research teams. In addition, the high safety profile observed in Phase I and Phase II clinical trials this far strongly anticipate that TB4 will be safe and efficacious at the applied local or systemic dose for broad clinical applications in the future.

We still do not know all the details regarding this special molecule; however, we genuinely believe there are more like it concealed in the human body, awaiting discovery. With their help, we may be capable of fulfilling our dream of reversing age.

Researchers here discuss the ongoing development of biomarkers of aging and age-related disease based on glycosylation of proteins, the attachment of a glycan to a protein. Various forms of post-translational modification occur to proteins throughout the body, changing their function, and are, to varying degrees on a case-by-case basis, necessary, tolerated, problematic, and targeted for removal by cell maintenance processes. These processes shift in response to the metabolic changes of aging, and at least some of them may useful as metrics of age-related degeneration and risk of age-related disease. At least one company, GlycanAge, works in this space, and there will likely be other similar efforts in the future.

Protein glycosylation is the biochemical process for which a carbohydrate molecule is covalently attached to a protein functional group. In biology, glycosylation mainly refers to the enzymatic process that binds glycans to proteins, affecting intracellular processes like folding and transport, and playing an important role in many cellular signaling and communication events.

Three major n-glycan structures present in human blood glycoproteins (serum, plasma, and immunoglobulins fraction) have shown clear changes with ageing. Agalactosyl n-linked oligosaccharides (NG0A2F and NG0A2FB) increase with age whereas core-fucosylated biantennary n-glycans (NA2F) decrease with age. A similar trend was observed in a study which aimed to evaluate the effects of the age and gender on the human serum n-glycans profiles: NGA2F and NGA2FB increased gradually with ageing whereas NA2F decreased. Additionally, before the age of 50 years these three glycans changed only slightly with age, but the difference between age groups 41-50 and 51-60 years was statistically significant, indicating that the age-related physiological changes occurred in the fifties.

An ageing biomarker named GlycoAgeTest has been developed, which could possibly forecast disease progression during ageing. This marker is the log of the ratio of two glycans (NGA2F and NA2F), which remains steady up to the age of 40 years and thereafter gradually increases to reach its highest level in nonagenarians. Furthermore, patients with dementia or Cockayne syndrome have shown to have a higher GlycoAgeTest level than age-matched healthy individuals. It was concluded that the value of GlycoAgeTest is better than chronological age for estimating the physiological age of a human individual, and that it could be used as an ageing biomarker for healthy humans.

Glycome analysis is emerging as a source of potential biomarkers in different pathological states. Its analysis is not easy, as the diverse structures of glycans are complex and heterogenic. Moreover, there is a wide range of possible monosaccharide combinations and linkages, that result in structurally complex glycans, which can be attached to proteins, conforming glycosylation post-translational modifications. In clinical studies, the comparison of glycans levels altered in specific diseases often leads to inconsistent results, which cannot be explained completely by the different statistical methods. This may be due to the diversity of the glycome in different populations and even in different environments. Furthermore, the use of a wide range of glycomic methodologies leads to low comparability between studies which hinders the production of clear results.

Link: https://doi.org/10.3390/ijms22115788

Some years back, the Methuselah Foundation partnered with NASA to launch the Vascular Tissue Challenge, to attempt to spur greater efforts on the part of research groups and companies working on the production of vascularized tissue. The presence of a sufficiently small-scale, dense vascular network is the limiting factor in the size of engineered tissue that can be produced via techniques such as bioprinting. Absent a capillary network, nutrients can only perfuse a few millimeters into solid tissue. Building a life-like vasculature of hundreds of tiny capillaries passing through every square millimeter of tissue in cross-section has proven to be a challenge, but one that numerous teams are now making meaningful progress towards solving.

Methuselah Foundation, which co-sponsored the Vascular Tissue Challenge with NASA, today announced the award-winning researchers achieved scientific breakthroughs that promise to dramatically change the future of human health. The first and second place Challenge winners announced by NASA today are the first scientific teams to engineer and sustain thick functioning human tissue in a lab. The Challenge, first conceived by Methuselah Foundation in 2013, was conducted to increase the pace of bioengineering innovations to benefit humans on Earth and future space explorers.

Eleven teams competed in the Challenge to produce an in-vitro, vascularized organ tissue that is more than 1 centimeter thick. Winning tissue had to provide adequate blood flow and survive at least 30 days. The first-place winner was Team Winston from the Wake Forest Institute for Regenerative Medicine, affiliated with Wake Forest School of Medicine. The team, led by Dr. James Yoo, was awarded $300,000. It will also receive $200,000 from CASIS (Center for the Advancement of Science in Space), to fund the cost of conducting a tissue generation experiment in zero gravity.

The second-place winner was Team WFIRM, also from the Wake Forest Institute for Regenerative Medicine. That team, led by Dr. Anthony Atala, was awarded $100,000. Both groups created lab-grown human liver tissues that were robust enough to survive and function like healthy liver tissue found inside our bodies. Winning entries were built using 3D printing technologies. Ongoing progress will ultimately enable physicians to 3D print human organs with a patient's unique DNA.

Link: https://www.prnewswire.com/news-releases/nasamethuselah-challenge-winners-make-history-by-engineering-sustaining-live-human-tissue-in-a-laboratory-301309212.html

The short version of the story regarding the failure of resTORbio's phase 3 trial of an mTORC1 inhibitor targeting immune function and influenza infection in old people is that the FDA forced a last minute change of the phase 3 endpoint from the phase 2 endpoint of a reduction in clinically confirmed infections to a more nebulous outcome of whether or not people reported feeling better. Which is far from the worst offense that FDA staff have committed in the course of hindering the adoption of new medical technologies, but it is illustrative of the obstacle that regulators pose. We can all speculate as to what was going on under the hood here, and which influences led to this outcome.

To my eyes, the field of mTOR based therapies remains something of a sideshow when it comes to human aging and longevity. The same is true of many of the metabolic manipulation approaches based on upregulation of stress response mechanisms. These mechanisms are known to produce sizable effects in short-lived species, but not in long-lived species such as our own. Thus here, mTORC1 inhibition does not produce a startling and large effect on infection rate and immune function, and nor should we expect it to, but it is cheap and it does produce some effect. mTORC1 inhibition replicates a thin slice of the beneficial calorie restriction response, and we know what calorie restriction can achieve in humans; this sort of approach isn't the path to very large gains.

We did a phase 2b and a phase 3 double-blind, randomised, placebo-controlled trial in adults aged at least 65 years enrolled in New Zealand, Australia, and the USA at 54 sites. In the phase 2b trial, patients were aged 65-85 years, with asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure, were current smokers, or had an emergency room or hospitalisation for a respiratory tract infection (RTI) within the past 12 months. In the phase 3 trial, patients were aged at least 65 years, did not have COPD, and were not current smokers.

In the phase 2b trial, patients were randomly assigned to using a validated automated randomisation system to oral RTB101 5 mg, RTB101 10 mg once daily, or placebo in part 1 and RTB101 10 mg once daily, RTB101 10 mg twice daily, RTB101 10 mg plus everolimus once daily, or matching placebo in part 2. In the phase 3 trial, patients were randomly assigned to RTB101 10mg once daily or matching placebo. The phase 2b primary outcome was the incidence of laboratory-confirmed RTIs during 16 weeks of winter cold and influenza season and the phase 3 primary outcome was the incidence of clinically symptomatic respiratory illness defined as symptoms consistent with an RTI, irrespective of whether an infection was laboratory-confirmed.

The purpose of our trials was to investigate whether targeting ageing biology with mTOR inhibitors could improve immune function and decrease the incidence of RTIs in older adults at doses that were well tolerated. The mTOR inhibitor RTB101 10 mg once daily for 16 weeks was well tolerated in adults aged at least 65 years, increased expression of IFN-stimulated antiviral genes in peripheral blood, and decreased the incidence of laboratory-confirmed RTIs (the phase 2b primary endpoint), but not the incidence of clinically symptomatic respiratory illness defined as respiratory symptoms consistent with an RTI irrespective of whether an infection was laboratory confirmed (the phase 3 primary endpoint).

Several possible explanations exist for the divergent results of the phase 2b and phase 3 trials, including the change in primary endpoint and changes in the way respiratory symptoms were collected between the two trials. In the phase 2b trial, respiratory illness symptoms were collected during twice weekly telephone calls with patients and the primary endpoint required predefined symptomatic criteria to be met as well as laboratory confirmation of an infection. In the phase 3 trial, respiratory illness symptoms were collected in eDiaries that patients filled out each evening and the primary endpoint was based on symptoms alone without requiring laboratory confirmation of an infection. Multiple investigators in the phase 3 trial anecdotally noted that patients reported in their nightly eDiary respiratory illness symptoms such as cough or headache that were part of the prespecified diagnostic criteria for a clinically symptomatic respiratory illness even when the patient and the investigator did not think that the patient had an RTI.

Despite the negative phase 3 results, important lessons were learned from this clinical development programme that is the largest to date targeting ageing biology in humans. First, the results show that it is possible to target mechanisms underlying ageing biology safely with therapies such as mTOR inhibitors in older adults. Second, the results suggest that therapies that target ageing biology in older adults might ameliorate at least some aspects of ageing organ system dysfunction (such as deficient IFN-induced antiviral responses). Further refinement of clinical endpoints and more precise identification of responder patient populations will be important in future trials of therapies that intervene in ageing biology to improve immune function in older adults.

Link: https://doi.org/10.1016/S2666-7568(21)00062-3

Somatic cells become senescent after reaching the Hayflick limit on replication. In the case of immune cells, that occurs more often in scenarios of infection or tissue damage that provoke an immune response and hence faster pace of replication. The central nervous system immune cells known as microglia are known to exhibit senescence in later life and neurodegenerative conditions, and the targeted elimination of these cells via senolytic therapies has been shown to reverse symptoms in animal models of these conditions.

Senescent cells secrete a mix of signals that produces chronic inflammation and disrupts tissue function; their presence is an important contributing cause of many age-related declines. Researchers here propose that replicative senescence of microglia is the connects forms of molecular damage and infection linked to Alzheimer's disease and the presence of senescent microglia that accelerate the condition. In other words that the immune response and increased pace of replication of microglia is an important factor in neurodegeneration.

The re-activation of microglial proliferative programs is the earliest response to pre-pathological events in chronic neurodegenerative diseases, with microglial proliferation increased in Alzheimer's disease (AD). Microglia have a very rapid proliferative response to the incipient accumulation of amyloid-β, during the onset of tau pathology, and in several other related models of neurodegeneration. We and others have demonstrated that the proliferation of microglia is a central contributor to disease progression. The inhibition of microglial proliferation, using CSF1R inhibitors, ameliorates amyloid and tau pathology, and has emerged as a promising target for clinical investigation.

Integrating our knowledge of microglial population dynamics renders an interesting hypothesis. When combined, the cycling events accumulated in microglia from development to disease would put these cells on a trajectory toward cellular senescence. Replicative senescence, the loss of mitotic potential accompanied by significant telomere shortening, occurs once a cell has undergone ∼50 replications, the so-called Hayflick limit. Thus, we hypothesized that the developmental setup of the population, combined with microglial turnover, would pre-condition these cells to undergo replicative senescence when challenged with additional proliferative events (i.e., as a consequence of brain pathology).

Some reports suggest that microglia show telomere shortening and decreased telomerase activity in both aging and end-stage AD. However, to date, no formal evidence has been provided supporting the idea that these progressive changes in the dynamics of microglia are driving the shift of the microglial response from beneficial to detrimental and therefore contributing to the initiation of AD.

Here, we provide evidence that microglia undergo replicative senescence in a model of AD-like pathology and in human AD. We demonstrate that microglia display a senescence-associated profile and that this is dependent on proliferation. Our data support that the early generation of senescent microglia contributes to the subsequent onset and progression of amyloidosis, as well as the associated neuritic damage that is observed in the early stages of AD.

Link: https://doi.org/10.1016/j.celrep.2021.109228

As the COVID-19 pandemic ran its course, and it became clear that mortality in the old and the obese was the result of a cytokine storm, there was some speculation that the use of senolytics to clear senescent cells from old tissues would be an appropriate treatment to reduce mortality. Here, researchers provide supporting evidence for this view, showing that senolytic treatment in old mice reduces coronavirus mortality, as well as mortality due to other viral infections.

The risk of suffering a fatal inflammatory event as the result of infection is higher in individuals with an existing high level of systemic inflammation - due to, for example, the accumulation of senescent cells in the body that occurs in later life. Senescent cells secrete pro-inflammatory signals that are an important contributing cause of the chronic inflammation of old age, as well as the raised inflammation that accompanies obesity.

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-senescent cells through a paracrine mechanism.

Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting senescent cells using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the senescent cell burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.

Link: https://doi.org/10.1126/science.abe4832

It is not particularly controversial to say that aging causes Alzheimer's disease, at least in the most common version of the condition in which there is no gene variant known to accelerate pathology. How exactly aging causes Alzheimer's disease is very much debated, however. This is not unusual; most age-related conditions have the same issue and the same debate.

The end stage pathology of age-related conditions is fairly well mapped, and we have a good idea as to what the root causes of aging are, the forms of damage and disarray that accumulate as a result of the operation of a normal metabolism. In between what is known of the cause and what is known of the end result, the map is poor at best, however. Drawing clear lines of cause and effect between those two areas of study remains very challenging. The operation of metabolism is ferociously complex, and deciphering cause and effect in a network of interacting processes is not as easy as one might think.

It is likely the case that even when the first body of rejuvenation therapies based on periodic repair of root cause damage exists and is widely used, there will still be debate and investigation over how exactly the processes of aging combine to cause the more complicated age-related conditions.

When aging switches on Alzheimer's

Aging increases the risk for developing Alzheimer's disease (AD). Pathological hallmarks of AD include abnormal deposits of extracellular beta amyloid (Aβ) plaques and intracellular neurofibrillary tangles, which are proposed to impair synaptic function to foster progressive cognitive impairment. Although aging and AD undeniably share a number of common features, such as oxidative stress, mitochondrial impairment, bioenergetic, and metabolic shifts, AD is not the inevitable co-morbidity of aging. This escape from AD arouses hope that anti-aging interventions could decelerate aging switches for AD dementia.

Our environment, lifestyle, stress, physical activity, and habits all modulate epigenetic control of gene expression for continuous environmental tracking. Age-related redox stress, often measured as oxidative stress in aging and AD, launches a global switch in the epigenetic landscape, widely affecting methylation, histone modification, and noncoding RNA regulation, to further drive downstream metabolic and energetic shifts.

According to a modified amyloid cascade hypothesis, amyloid-mediated oxidative stress triggers a cascade of downstream effects including mitochondrial dysfunction, excitotoxicity, synaptic loss, and neuroinflammation. However, the failure of anti-amyloid and anti-inflammatory therapy in clinical trials allows us to entertain other causal possibilities including an age-related oxidative redox shift as an upstream switch that changes amyloid processing, deposition, or clearance. Intriguingly, some resilient older individuals present with similar loads of Aβ and tangles compared to AD cases without experiencing dementia.

Further studies in resilient brains point out distinct upregulation of anti-inflammatory cytokines in entorhinal cortex, increased expression of neurotrophic factors and reduced expression of chemokines linked to microglial recruitment, which all suggest activated neuroglial inflammation in non-resilient AD. Since inflammation is switched on by an oxidative redox state, normal microglia that selectively remove excitotoxic synapses could be over-activated toward inflammatory neurodegeneration in AD. Suitable redox markers could enable measured redox therapies to decelerate inflammation and the neurodegenerative cascade.

There has been some research into the use of ultrasound for short-term disruption of the blood-brain barrier, to allow medication through without excessive delivery of unwanted materials into the central nervous system. In the course of this line of work, researchers observed that ultrasound treatments resulted in improved cognitive function in mice. Here, it is suggested that this has nothing to do with the blood-brain barrier effects, but instead it is in some way upregulating neurogenesis, the production of new neurons and their integration into neural circuits in memory-related areas of the brain. The present view on neurogenesis is that more of it would be a good thing, even in youth, and the decline of neurogenesis with age is an unfortunate outcome that should be prevented. Might suitable ultrasound treatments have a large enough effect to matter in humans? Perhaps; it is certainly an interesting proposal.

The idea that sound waves knocking at the skull could boost memory continues to sound far-fetched to many Alzheimer's researchers, but researchers report that scanning ultrasound improved synaptic signaling, increased neurogenesis, and sharpened spatial memory in old wild-type mice. Importantly, this worked without breaching the blood-brain barrier, a commonly used ultrasound trick to provoke a brain response. Whether this technique is appropriate for people remains to be seen, though early stage clinical trials in older adults indicate it may be safe.

Previous work had suggested ultrasound somehow opens TRPA1 calcium channels in astrocytes, which then release glutamate to activate NMDA receptors on nearby neurons. Researchers looked for signs of astrocyte-mediated activation in mouse hippocampal tissue via Western blots, and found that tissue from mice exposed to ultrasound contained more TRPA1 than tissue from control.

Evidence of NMDA activation came when the scientists separated hippocampal tissue into total and postsynaptic fractions. In the postsynaptic fraction, ultrasound had bumped up the amount of NR2B, a subunit of NMDA receptors that is needed for long-term potentiation (LTP), a form of synaptic plasticity. LTP is crucial for learning and memory and by 20 months of age, it has faded. However, the scanning ultrasound had restored LTP in aged mice, as judged by evoked potentials in hippocampal slices. Based on dentate gyrus expression of doublecortin, a marker of new neurons, the authors concluded that ultrasound upped neurogenesis 13-fold. The scientists did not track how long the memory changes lasted. "Because there are changes at the NDMA receptor level, my gut feeling is that ultrasound leads to long-lasting changes."

Link: https://www.alzforum.org/news/research-news/no-breach-needed-ultrasound-improves-memory-mice

Kidney function is very important to long-term health, influencing the operation of other organs. This is well illustrated by research into klotho, a longevity associated gene that appears to primarily function in the kidney, yet improves numerous measures of cognitive and cardiovascular aging when highly expressed. Here, researchers show that epigenetic age acceleration, in which epigenetic age is higher than chronological age, is associated with worse kidney function. Epigenetic age is in effect an assessment of cellular reactions to the aged tissue environment of damage, dysfunction, and altered signaling, and it is interesting to see it reflect kidney function in this way.

The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.

We identified 23 significant associations in our large trans-ethnic meta-analysis with a consistent direction of effect across studies. Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as the 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate).

Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging, and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

Link: https://doi.org/10.1186/s13148-021-01082-w

Aging is poorly defined as anything other than an outcome, as is pointed out in today's open access paper. Aging is the rise in mortality risk due to intrinsic causes over time, a definition that is hard to argue with, but that provides next to no insight. There are more complicated and detailed definitions, but near all are all quite similar in being a catalog of symptoms rather than a catalog of processes. The SENS view of aging, on the other hand, is in fact a list of causative processes, but is by no means widely agreed upon, nor expected to remain unchanged by later data.

Definitions of aging that are in effect a taxonomy, in the sense that we put these humans into the "old" bucket because they exhibit measurable symptoms A through Z, are really not helpful at all when it comes to the development of therapies to treat aging. One needs to know what to target. What processes must be interrupted? What damage must be repaired? This is the entire point of the SENS view of aging: that we need this description of aging as a set of processes, rather than as a set of symptoms, in order to even start building effective rejuvenation therapies.

Sadly, validating a consensus definition of aging is only going to be achieved via the production of working rejuvenation therapies. If one repairs a form of damage and that actually works to produce rejuvenation, then that is supportive of definitions of aging that include that specific form of damage. It seems likely to me that there will be active debate over the causes of aging all the way through the process of producing a first generation package of good-enough rejuvenation therapies that adds decades to healthy life spans. That active debate will take place alongside a great deal of wasted research and development effort, as people attempt to validate incorrect approaches.

The SENS view of aging is very important, not just because its conclusions as to areas of study and forms of therapy seem likely to be the best way forward to practical human rejuvenation, but also because, philosophically, everyone else should stop building taxonomies of aging and start thinking about causes and processes of aging. It will be a messy process all the way from here to the goal of physical immortality and medical control of aging, but it seems that there could be a lot less wasted effort along the way than is presently the case. Incidentally, the paper noted here starts off well, and is an interesting read, but then falls into the pit of suggesting that aging is an intrinsic property of life, and thus not amenable to effective treatment.

An essay on the nominal vs. real definitions of aging

Several recent publications, including the one entitled "What if there is no such thing as aging?", have brought out an astonishing trend: the mere existence of biological aging is being questioned. The title reiterates the famous proposition "There is no such thing as aging and cancer is not related to it", and the paper suggests that the same is relevant to the other age-associated conditions: "...we are not studying a single biological phenomenon, but an assortment of loosely related processes that we find convenient to lump together"; ultimately, "... the concept of aging does not reflect any underlying biological reality".

Being intentionally provocative, the paper does however reflect the trend, which is developing, paradoxically, in parallel with the increasing prevalence of aged people in the world and with the recently emerged discipline called "geroscience". According to the geroscience agenda, the best way to combat the most prevalent age-associated conditions, such as atherosclerosis, cancer, type II diabetes, and neurodegeneration, is to target their common risk factor rather than each of the conditions specifically. The common risk factor is aging.

Apart of that the very practice of piling up of newly invented scientific disciplines and respective terms is questionable, a problem with the geroscience agenda relates to the feasibility of evaluating the benefits of its implementation. The benefits of targeting of a disease may be evaluated, based on its commonly accepted definition (diagnostic criteria), as a decrease in the incidence of cases recognized according to this definition. Can we decrease the incidence of aging otherwise than by making people dead before they get old? Any answer to this question depends on the criteria used to distinguish (i) aging from all the rest that may occur to living bodies and (ii) living bodies from all other kinds of bodies, in other words, on the definition of (biological) aging. The lack of consensus on the definition of aging is long recognized and has recently been highlighted by asking several basic questions about aging to recognized authorities in aging research. Answers to each of the questions differed up to antipodal extremes.

Based on several scores of definitions found in the most highly cited (that is the most representative and influential) papers on aging, the following features commonly used to define aging have been distinguished: (1) structural damage, (2) functional decline, (3) depletion of a reserve required to compensate for the decline, (4) typical phenotypic changes or their cause, and (5) increasing probability of death. Noteworthy, these characteristics are not really five definitions of aging, but rather five defining features of aging. This the above inventory to the kind of definitions that in philosophy of science is known as "nominal" and is opposed to "real"

By its nominal definition, water is a colorless and odorless liquid having defined specific gravity, viscosity etc. By its real definition, water is a compound comprised of two hydrogen atoms and one oxygen atom connected in a certain order. Noteworthy, the real definition is senseless for people ignorant of atoms. Likewise, the nominal definition of aging as a set of observable features should be supplemented, if not replaced, with its real definition. The latter is suggested here to imply that aging is the product of chemical interactions between the rapidly turning-over free metabolites and the slowly turning-over metabolites incorporated in macromolecules involved in metabolic control.

The phenomenon defined in this way emerged concomitantly with metabolic pathways controlled by enzymes coded for by information-storing macromolecules and is inevitable wherever such conditions coincide. Aging research, thus, is concerned with the elucidation of the pathways and mechanisms that link aging defined as above to its hallmarks and manifestations, including those comprised by its nominal definitions. Esoteric as it may seem, defining aging is important for deciding whether aging is what should be declared as the target of interventions aimed at increasing human life and health spans.

Here is a theory as to why, in this era of rejuvenation research and a growing longevity industry, most people continue to say that they would not wish to take advantage of medical technologies that allowed for a radical life extension of decades or centuries. We as a species discount the value of future gains quite aggressively. Being alive and in good health three decades from now is just not worth that much to the processes in our minds that assess values and balance them against actions and goals. Conforming to common behaviors in the primate hierarchy here and now, such as by not saying things that are too far out of the ordinary for one's demographic and peer group, will tend to win out. Most people will value present declarations of conformity more than they value any future gain in health and longevity.

Biomedical technology holds the promise of extending human life spans; however, little research has explored attitudes toward life extension. Investigated attitudes toward life extension about young adults, younger-old adults, and older-old adults. This survey asked young adults (n = 593), younger-old adults (n = 272), and older-old adults (n = 46) whether they would take a hypothetical life extension treatment as well as the youngest and oldest age at which they would wish to live forever.

Age cohorts did not vary in their willingness to use life extension; however, in all three age cohorts, a plurality indicated that they would not use it. Men indicated a higher level of willingness to use the life extension treatment than women. Younger-old and older-old adults indicated that they would prefer to live permanently at an older age than younger adults. If a life extension treatment were to become available that effectively stopped aging, young adults may be likely to use such a treatment to avoid reaching the ages at which older cohorts say they would prefer to live forever.

Link: https://doi.org/10.1016/j.jaging.2021.100931

While it may or may not turn out to hold true for every stem cell population in the body, there is a fair amount of evidence for muscle stem cells to remain competent and in principle capable of maintaining tissue well into later life. The loss of function that we observe in muscle tissue in old age is much more a matter of inactivity rather than incapacity. This inactivity may be an evolved response to a damaged environment, lowering cancer risk at the expense of a slow decline into frailty, or it may be the consequence of age-related molecular damage rising to pathological levels in the stem cell niche tissue, or both. That stem cells remain capable in old tissue suggests a shorter path to useful regenerative therapies - building treatments that work by rousing existing cells to action, rather than having to deliver new cells.

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration.

In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.

Link: https://doi.org/10.1111/acel.13411

A few years back, researchers noted that a common growth hormone receptor gene variant was associated with greater life expectancy in humans. There was some theorizing as to possible mechanisms at the time, following the usual paths for anything that touches on growth hormone or its receptor. In short-lived mammals such as mice, loss of function in growth hormone or its receptor produces small body size and increased healthy longevity. The present record for mouse longevity is held by a growth hormone receptor knockout lineage. In humans, members of the small Laron syndrome population exhibit an analogous disruption of growth hormone metabolism, and while there are signs that they might be more resistant to some forms of age-related disease, they do not live notably longer than the rest of us. It is usually the case that metabolic alterations of this nature, in this part of metabolism, have large effects in short-lived species and much smaller effects in long-lived species.

Given the example of Laron syndome to suggest that the usual explanations regarding growth hormone metabolism may not be useful here, how might variants in the growth hormone receptor gene actually produce an effect on human longevity? Researchers have been working to answer that question, and in today's open access paper it is proposed that some variants reduce the negative impacts of raised blood pressure, or hypertension. Blood pressure is very influential on health and mortality in later life. Raised blood pressure causes damage to delicate tissues in organs throughout the body, and particularly in the brain. It also accelerates the progression of atherosclerosis, and makes it more likely that atherosclerotic vessels burst or become blocked. It also contributes to heart failure. Hypertension causes so many forms of downstream damage that control of raised blood pressure via current standards of medication, approaches that in no way address the underlying causes of the condition, can nonetheless reduce mortality risk by a sizable amount.

Association of growth hormone receptor gene variant with longevity in men is due to amelioration of increased mortality risk from hypertension

Growth hormone (GH) and its receptor (GHR) are not only important for regulating growth, they have many other important biological functions including response to nutrients, regulation of metabolism, and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. Growth hormone signaling is an important regulator of aging. GH deficiency leads to slower growth, delayed maturation, reduced body size, and can result in attenuation of the rate of aging, increased health-span, and increased longevity. Key to this are evolutionarily conserved pathways of insulin/insulin-like growth factors and mechanistic target of rapamycin, where there are trade-offs between anabolic processes/growth and lifespan.

We have reported a significant negative association between height and longevity in our large cohort of American men of Japanese ancestry. More recently, in a case-control study of 13 single nucleotide polymorphisms (SNPs) of GHR in this cohort, SNP rs4130113 was associated with greater lifespan of nonagenarian men aged ≥ 95 years. In the present longitudinal study, we tested the hypothesis that genetic variation in GHR affects lifespan at least in part by protection against the detrimental effects of one or more aging-related diseases, namely diabetes, hypertension, coronary heart disease, and/or cancer.

The present study has found that the longevity-associated AA genotype (frequency 35.3%), but also the GG genotype (frequency 17.1%), of GHR SNP rs4130113 is associated with protection against risk of mortality in hypertensive elderly American men of Japanese ancestry. As a result, those individuals lived longer, whereas individuals with the AG genotype (frequency 47.6%) died sooner. Moreover, the survival curve for hypertensive AA/GG subjects did not differ significantly from the survival curve for normotensive subjects with the AA/GG genotype. This indicated that possession of the GHR longevity-associated genotype can mitigate the adverse effects on lifespan of having hypertension.

The mechanisms of aging produce a range of detrimental effects on bones, most evidently the progressive loss of density and resilience that becomes osteoporosis in its later and severe stages. It is known that strength training blunts the loss of muscle mass and strength that occurs with age, and reduces mortality risk in later life. Here, researchers show that it can also slow the aging of bone tissue. The effect size is small, but note that the researchers are comparing well trained athletes with adequately trained athletes, rather than with the general population.

Cross-sectional and interventional studies suggest that high-intensity strength and impact-type training provide a powerful osteogenic stimulus even in old age. However, longitudinal evidence on the ability of high-intensity training to attenuate age-related bone deterioration is currently lacking. This follow-up study assessed the role of continued strength and sprint training on bone aging in 40- to 85-year-old male sprinters (n = 69) with a long-term training background.

Peripheral quantitative computed tomography (pQCT)-derived bone structural, strength, and densitometric parameters of the distal tibia and tibia midshaft were assessed at baseline and 10 years later. The groups of well-trained (actively competing, sprint training including strength training ≥2 times/week; n = 36) and less-trained (less than 2 times/week, no strength training, switched to endurance training; n = 33) athletes were formed according to self-reports at follow-up. Longitudinal changes in bone traits in the two groups were examined.

Over the 10-year period, group-by-time interactions were found for distal tibia total bone mineral content (BMC), trabecular volumetric bone mineral density (vBMD), and compressive strength index, and for mid-tibia cortical cross-sectional area, medullary area, total BMC, and BMC at the anterior and posterior sites. These interactions reflected maintained (distal tibia) or improved (mid-tibia) bone properties in the well-trained and decreased bone properties in the less-trained athletes over the 10-year period. Depending on the bone variable, the difference in change in favor of the well-trained group ranged from 2% to 5%.

In conclusion, our longitudinal findings indicate that continued strength and sprint training is associated with maintained or even improved tibial properties in middle-aged and older male sprint athletes, suggesting that regular, intensive exercise counteracts bone aging.

Link: https://doi.org/10.1002/jbm4.10513

One can't maintain dismissive skepticism forever in the face of scientific and medical development communities that are ever more engaged in the development of therapies to address the mechanisms of aging. To pick one example, senolytic treatments that clear senescent cells from aged tissues are producing consistently amazing data in mice: rejuvenation, extension of healthy life, reversal of measures of many specific age-related diseases. We'll soon know how well the more viable senolytics perform in human trials, as the preliminary data from the use of dasatinib and quercetin shows that it does selectively destroy senescent cells in humans as it does in mice. Given the serious prospect of living longer in good health, I would expect the previously doom and gloom crowd of naysayers to capitulate and admit that, yes, actually it would be pleasant to have more health, more life, and less pain, suffering, and death.

People are living longer, staying healthier longer and accomplishing things late in life that once seemed possible only at younger ages. And it's not just superstars. The fraction of over-85s in the U.S. classified as disabled dropped by a third between 1982 and 2005, while the share who were institutionalized fell nearly in half. As a whole, Americans seem to be aging more slowly than before. Researchers compared how men 60 to 79 years old aged in 1988 to 1994 and in 2007 to 2010. They found that in those later years, the men they studied had a biological age four years less than the men in the earlier years, in part because of improvements in lifestyle and medications. This suggests that not only are people living longer, they're also staying healthier longer.

On one level, greater health and longevity is an old story. In 1900, life expectancy in the U.S. was about 47 years and now it's about 78. But we may also be on the cusp of something new. Over the course of the 20th century, we primarily aided longevity by tackling disease. In the first half of the century vaccines and other innovations prevented people from dying young of communicable diseases. In the second half, improvements in lifestyle and other medical breakthroughs prevented many people from dying in middle age of things like heart attacks and cancer.

But while these improvements have made it more likely that people will live to be 65, after that, aging itself takes an inexorable toll. Even if you beat lung cancer or survive a heart attack, your body's deterioration will finish you off before too long. The average 80-year-old suffers from around five diseases. That's why even if we could totally cure cancer, it would add less than three years to average life expectancy. A total cure for heart disease would give us at best two extra years. To keep the longevity train rolling it may not be enough to cure diseases. We may also need to address the underlying condition of aging itself, which is, after all, the primary risk factor for late-life decline.

S. Jay Olshansky has said "While there are no documented interventions that have been proven safe and effective in slowing aging in humans today, we are on the verge of a breakthrough." For example, as we age, we build up more and more "senescent" cells, which secrete inflammatory molecules that can effectively accelerate aging. In 2011, researchers removed these cells from mice and extended their life spans. Clinical trials on people began in 2018. It's likely that all Americans could be living longer, healthier lives. I imagine an 80-year-old bounding from bed, biking in the morning and playing softball in the afternoon. We're all on borrowed time. More time is more life, and more of it will be sweet.

Link: https://www.nytimes.com/2021/06/03/opinion/age-life-expectancy.html