Fight Aging!

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Contents

• Relating Warfarin, Vitamin K, and Cellular Senescence in the Progression of Aortic Calcification
• MYSM1 Overexpression Extends Life in Mice via a Reduced Senescent Cell Burden
• Glucosamine Use Correlates with a Sizable Reduction in Mortality, but Not Yet Convincingly
• Continuing to Search for a Point of Intervention in Alzheimer's Disease at which Removing Amyloid-β Will Work
• A Demonstration of Reduced Cerebrospinal Fluid Flow through the Cribriform Plate in Aged Mice
• Thymic Involution and the Decline of the Immune System with Age
• BioAge Raises $90M and Prepares for Clinical Trials of Small Molecules to Slow Effects of Aging
• How Much of Cognitive Decline is Actively Maintained via Dysfunctional Cell States or Signaling, and is thus Quickly Reversible?
• GATA6 in the Mechanisms of Functional Rejuvenation of Cell Properties via Reprogramming
• The Connected Age-Related Atrophy of Thymus and Pineal Gland
• IL-6 Contributes to Age-Related Loss of Mitochondrial Function in Cerebral Vasculature
• Senescent Cells Fail to Maintain Proteostasis
• An Interview with Alex Zhavoronkov of Insilico Medicine
• Analysis of Human Inheritance of Longevity is not as Straightforward as One Might Think
• HAND2 Overexpression in Sympathetic Neurons Slows the Onset of Sarcopenia in Aged Mice

Relating Warfarin, Vitamin K, and Cellular Senescence in the Progression of Aortic Calcification
https://www.fightaging.org/archives/2020/12/relating-warfarin-vitamin-k-and-cellular-senescence-in-the-progression-of-aortic-calcification/

Calcification of blood vessel walls progresses with age, an issue that sees cells behave as through they are in bone tissue, a maladaptive reaction to the altered signaling environment and damage of aged tissue. The resulting deposition of calcium makes normally flexible cardiovascular tissue stiff and dysfunctional, ultimately contributing to disease and death. Evidence has accumulated in recent years for the accumulation of senescent cells to be an important contributing factor to calcification. Senescent cells grow in number with age and secrete the senescence-associated secretory phenotype (SASP), signals that rouse the immune system to inflammation and cause harmful alterations in the behavior of other cells.

There is an established body of work regarding factors that affect the progression of calcification, such as chronic use of the anticoagulant warfarin (unfavorable) and vitamin K intake (favorable). Given the better and broader understanding lately emerged in the research community of the relevance of cellular senescence to aging, a great deal of retrofitting of old theories and data is presently taking place. Today's open access paper is an example of this sort of work, in which links are established between the SASP and long-established risk factors for calcification revolving around the role of vitamin K and treatments like warfarin that reduce vitamin K levels.

Warfarin Accelerates Aortic Calcification by Upregulating Senescence-Associated Secretory Phenotype Maker Expression

Aortic calcification (AC) is a pathological condition with increasing prevalence of morbidity and mortality. AC is a process of osteoblast-like cell accumulation in the muscular layer of arteries. Enhanced stiffness of the arteries in AC might lead to severe vascular complications in the brain, heart, and kidneys. AC is a strong, independent predictor of cardiovascular disease (CVD) and cardiac adverse events. The present study demonstrated that the association of warfarin use with AC differs in different age groups of patients. Specifically, warfarin adversely affects younger (under 65 years) patients more than older (over 65 years) patients, and this is possibly due to the fact that warfarin-associated senescence was more sensitive in younger patients. In vitro study also revealed that young VSMC are more sensitive to warfarin-induced low-grade calcification.

It has been observed that there is a systemic increase level of secreted proteins with aging, which contain several proinflammatory cytokines, chemokines, tissue-damaging proteases, and growth factors. These secreted factors affect the microenvironment of tissue, in which they could propagate the stress response and regulate neighboring cells. These phenotypes are termed the senescence-associated secretory phenotype (SASP). The SASP is a critical intrinsic characteristic of cellular senescence resulting in a chronic low-grade state of inflammation that has been implicated in the development of several chronic diseases of aging including AC. Among SASP, cytokines and growth factors are important in the differentiation of senescent VSMC into calcified cells.

we conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis (MESA); 6,655 participants were included. From MESA data, we found that AC was related to both age and vitamin K; furthermore, the score of AC increased with SASP marker including interlukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) rising. Next, a total of 79 warfarin users in our center developed significantly more calcified coronary plaques as compared to non-warfarin users. We investigated the role of warfarin in phosphate-induced AC in different ages by in vitro experimental study. Furthermore, dose-time-response of warfarin was positively correlated with AC score distribution and plasma levels of the SASP maker IL-6 among patients younger than 65 years, but not among patients older than 65 years. In addition, in vitro research suggested that warfarin treatment tended to deteriorate calcification in young VSMC at the early stage of calcification. Our results suggested that aging and warfarin-treatment were independently related to increased AC. Younger patients were more sensitive to warfarin-related AC than older patients, which was possibly due to accumulated warfarin-induced cellular senescence.

In the MESA, we discovered that the accumulated intake of vitamin K was negatively related to AC, which demonstrated that warfarin may aggravate AC by downregulating the level of vitamin K in plasma. In addition, IL-6 and TNF-α levels were positively correlated with AC. When we divided individuals depending on vitamin K intake and analyzed the relationship among vitamin K, AC, and SASP, results showed that Agatston score (a measure of AC) and SASP level decreased with the increase of vitamin K intake.

MYSM1 Overexpression Extends Life in Mice via a Reduced Senescent Cell Burden
https://www.fightaging.org/archives/2020/12/mysm1-overexpression-extends-life-in-mice-via-a-reduced-senescent-cell-burden/

Senescent cell accumulation is an important cause of degenerative aging. Senescent cells cease replication and begin to secrete an inflammatory mix of signals that disrupt tissue structure and function. These cells are created constantly, largely as a result of somatic cells hitting the Hayflick limit on cellular replication, but also as a result of injury, molecular damage, inflammation, and the like. Near all senescent cells are rapidly destroyed, either via programmed cell death mechanisms, or via the immune system. This clearance falters with age, however, slowing down, becoming less efficient, and allowing senescent cells to accumulate, disrupt tissue function, and provoke chronic inflammation.

The targeted destruction of senescent cells has been shown - in animal models - to reverse the progression of many age-related conditions and extend healthy life span. It is easy to demonstrate such results, and many research groups have used many different methods to destroy senescent cells. To the extent that these errant cells are removed, benefits follow. As these demonstrations have accumulated over the years, researchers have broadened their investigations of the biochemistry of senescent cells.

One class of outcome of this work is represented by today's open access paper. Researchers have identified a gene that affects the burden of cellular senescence, and find that adjusting expression levels down or up also adjusts lifespan as well, due to there being greater or lesser numbers of senescent cells present in older individuals. This is a good secondary demonstration of the importance of senescent cells to aging and longevity, but not really a good basis for building interventions. Senolytic therapies that destroy senescent cells are just too good a class of treatment to see much competition from this front. In the case of senolytics: large beneficial effects are achieved very quickly; treatment is only needed intermittently, such as once every few months at most; the first generation drugs cost very little. That compares very favorably with a senescence suppression treatment that would have to be taken continuously across a lifetime, with only small benefits in the short term, particularly given that senescent cells are actually beneficial for wound healing and cancer suppression when present in small numbers, and briefly.

MYSM1 Suppresses Cellular Senescence and the Aging Process to Prolong Lifespan

Aging is characterized by a functional decline across multiple organ systems and is a risk factor for many human diseases. Substantial evidence has demonstrated that senescence is a key hallmark of the aging process and plays a critical roles in controlling aging and aging-associated diseases. Senescence is a cellular response that acts to restrict the proliferation of aged and damaged cells, and is also a state of growth arrest and pro-inflammatory cytokine release in response to stresses. One hallmark of cellular senescence is the secretion of excessive proinflammatory cytokines, chemokines, extracellular matrix proteins, growth factors, and proteases termed the senescence-associated secretory phenotype (SASP). Senescence constitutes a stress response triggered by insults associated with aging including genomic instability and telomere attrition.

DNA damage is a causal factor in the aging process that drives cells into senescence or apoptosis as results of the DNA damage response (DDR) controlled by DNA repair processes. DNA double-strand break (DSB) repair is known to decline age, leading to the accumulation of genomic rearrangements. Mutations in DNA DSB repair genes reduce lifespan, indicating that DNA repair pathways play a critical roles in the aging process.

The Myb-like, SWIRM, and MPN domains-containing protein 1 (MYSM1) is a histone 2A (H2A) deubiquitinase that specifically deubiquitinates H2A. It is a key functional regulator of hematopoietic stem cells, lymphocytes, and blood cells, and serves as an important regulator of tissue differentiation. MYSM1 is also linked to heritable bone marrow failure syndromes, plays a role in regulating skin development in mice, and impedes antiviral signaling. Loss of Mysm1 has been shown to promote activation of the p53 stress response and induced abnormal cell development and tissue differentiation. More recently, a study revealed that Mysm1 levels increase in response to etoposide-induced DNA damage and that mice lacking Mysm1 show a shorter lifespan. These important roles of MYSM1 implicate that it may be involved in the regulation of cellular senescence and the aging process.

The present study showed that MYSM1 is a key suppressor of senescence and aging. Functionally, MYSM1 functionally represses DDR-associated SASP and the aging process. Mechanistically, MYSM1 represses the aging process by promoting homologous recombination (HR) mediated DNA repair. Mysm1 deficiency promotes aging and aging-related pathologies and reduces lifespan in mice. AAV9-Mysm1 was shown to attenuate the aging process to prolong the lifespan of mice. Our data suggest that Mysm1 is a potential agent for the prevention of aging and aging-related diseases.

Glucosamine Use Correlates with a Sizable Reduction in Mortality, but Not Yet Convincingly
https://www.fightaging.org/archives/2020/12/glucosamine-use-correlates-with-a-sizable-reduction-in-mortality-but-not-yet-convincingly/

Researchers here note a study population in which glucosamine use correlates with a reduction in mortality risk that is of a similar size to that associated with exercise. One always has the suspicion that, even after controlling for such things, the use of less common supplements is just a marker for the small number of people who really care about their health, and who are putting in more effort across the board to maintain themselves. To become convinced that this is not the case, many studies producing similar results would have to exist, with many more participants taking glucosamine.

Consider the level of evidence for exercise to be similarly beneficial: dozens of studies, and hundreds of thousands of participants. Currently there are only a few such studies for glucosamine, and the one here is much less convincing than the other example published earlier this year, in which there were many more participants taking glucoseamine.

If we are to speculate on why glucosamine might have any sizable beneficial effect on health and mortality, then the first mechanism to consider is some form of reduction in the chronic inflammation that accompanies aging. Continual, unresolved inflammation is very disruptive to tissue function, and drives the onset and progression of all of the common age-related conditions. Glucosamine is used in connection with arthritis and other inflammatory conditions, but the evidence is very mixed for it to have any meaningful benefit there. This is another reason to be skeptical. If there were a sizable, reliable reduction in inflammation accompanying the supplementation of glucosamine, then it would show up in that data. And it doesn't.

https://wvutoday.wvu.edu/stories/2020/12/01/glucosamine-may-reduce-overall-death-rates-as-effectively-as-regular-exercise-says-wvu-study

Glucosamine supplements may reduce overall mortality about as well as regular exercise does, according to a new epidemiological study. Researchers assessed data from 16,686 adults who completed the National Health and Nutrition Examination Survey from 1999 to 2010. All of the participants were at least 40 years old. Researchers merged this data with 2015 mortality figures. After controlling for various factors - such as participants' age, sex, smoking status and activity level - the researchers found that taking glucosamine/chondroitin every day for a year or longer was associated with a 39 percent reduction in all-cause mortality. It was also linked to a 65 percent reduction in cardiovascular-related deaths. That's a category that includes deaths from stroke, coronary artery disease, and heart disease, the United States' biggest killer.

Glucosamine/Chondroitin and Mortality in a US NHANES Cohort

Limited previous studies in the United Kingdom or a single US state have demonstrated an association between intake of glucosamine/chondroitin and mortality. This study sought to investigate the association between regular consumption of glucosamine/chondroitin and overall and cardiovascular (CVD) mortality in a national sample of US adults. Combined data from 16,686 participants in National Health and Nutrition Examination Survey 1999 to 2010, merged with the 2015 Public-use Linked Mortality File. Cox proportional hazards models were conducted for both CVD and all-cause mortality.

In the study sample, there were 658 (3.94%) participants who had been taking glucosamine/chondroitin for a year or longer. During followup (median, 107 months), there were 3366 total deaths (20.17%); 674 (20.02%) were due to CVD. Respondents taking glucosamine/chondroitin were less likely to have CVD mortality (hazard ratio [HR] = 0.51). After controlling for age, use was associated with a 39% reduction in all-cause (HR = 0.61) and 65% reduction (HR = 0.35) in CVD mortality. Multivariable-adjusted HR showed that the association was maintained after adjustment for age, sex, race, education, smoking status, and physical activity (all-cause mortality, HR = 0.73; CVD mortality, HR = 0.42).

Continuing to Search for a Point of Intervention in Alzheimer's Disease at which Removing Amyloid-β Will Work
https://www.fightaging.org/archives/2020/12/continuing-to-search-for-a-point-of-intervention-in-alzheimers-disease-at-which-removing-amyloid-%ce%b2-will-work/

The dominant view of Alzheimer's disease remains the amyloid cascade hypothesis: amyloid-β accumulates over time in the brain, which generates immune dysfunction, inflammation, and finally tau aggregation that kills large numbers of brain cells. After a great deal of work and expense, the research and development community has produced a number of immunotherapies capable of reducing levels of amyloid-β in the brain. Unfortunately, these treatments don't appear to do all that much to improve the symptoms of Alzheimer's disease in patients. There is certainly no clear and evident gain in function across the board, and even where clinical trial data is sliced finely to try to uncover a subpopulation in which benefits do occur, these benefits are not large.

One hypothesis on this lack of efficacy is that only early intervention will work, given that Alzheimer's develops over years of growing levels of amyloid-β, while in later stages it is the case that chronic inflammation and tau aggregation become the driving mechanisms causing neurological dysfunction and cell death. An alternative hypothesis is that amyloid-β aggregation is a side-effect, of little importance to outcomes, while some combination of persistent infection, cellular senescence, and chronic inflammation are the primary mechanisms of Alzheimer's disease.

Given therapies that can reduce amyloid-β levels in the brain, and given a huge sunk cost to date in targeting amyloid-β, it is certainly the case that the early intervention hypothesis is going to be tested aggressively. Big Pharma entities are in search of some way to recoup the costs incurred to date, by demonstrating a beneficial use for these treatments. Today's research materials are one illustrative example selected from a broad range of efforts to find viable points of intervention in the very early development of Alzheimer's disease, with an eye to preventing the condition from progressing.

The Long Road to Dementia

Alzheimer's disease develops over decades. It begins with a fatal chain reaction in which masses of misfolded beta-amyloid proteins are produced that in the end literally flood the brain. Researchers have found that this chain reaction starts much earlier in mice than commonly assumed. This means that in addition to the well-known early phase of the disease with protein deposits but without symptoms of dementia, there is an even earlier phase in which the chain reaction is triggered by invisible tiny seeds of aggregation.

searched among the already known antibodies directed against misfolded beta-amyloid proteins for antibodies that can recognize and possibly also eliminate these early seeds of aggregation that currently escape biochemical detection. Of the six antibodies investigated, only aducanumab had an effect: Transgenic mice that were treated for only 5 days before the first protein deposits manifested, later on in life showed only half of the usual amount of deposits in their brains. "This acute antibody treatment obviously removes seeds of aggregation, and the generation of new seeds takes quite some time, so that much less deposits are formed in the weeks and months after the treatment. Indeed, the mice had only half the brain damage six months after this acute treatment."

Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life

Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer's disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease - currently defined as Aβ deposition without clinical symptoms - may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.

A Demonstration of Reduced Cerebrospinal Fluid Flow through the Cribriform Plate in Aged Mice
https://www.fightaging.org/archives/2020/12/a-demonstration-of-reduced-cerebrospinal-fluid-flow-through-the-cribriform-plate-in-aged-mice/

Neurodegenerative conditions are characterized by increasing amounts of molecular waste in the brain, such as amyloid-β, α-synuclein, tau, and a few others. In the case of Alzheimer's disease, evidence suggests that the condition starts because the drainage of cerebrospinal fluid (CSF) out of the brain through the cribriform plate declines with age. The plate becomes ossified and less porous as the inflammatory, altered biochemistry of aging changes cell behavior for the worse. This loss of drainage allows many varied forms of molecular waste to build up to harmful levels in at least some parts of the brain.

The cribriform plate isn't the only path by which CSF drains from the brain, but it is the one that drains the area of the brain, the olfactory bulb, where Alzheimer's pathology and amyloid-β aggregation first develops. The biotech startup Leucadia Theraputics was founded to develop assays and therapies based on this view of the origin of Alzheimer's disease. The staff there have demonstrated - in ferrets rather than mice, because mice don't normally exhibit any of the biochemistry of Alzheimer's disease - that artificially blocking drainage through the cribriform plate causes an accelerated buildup of molecular waste and cognitive impairment.

Today's open access materials, from another team, provide good supporting evidence for the CSF drainage view of Alzheimer's disease. The researchers show that the ossification of the cribriform plate with age in mice clearly reduces CSF drainage. We'd expect to see much the same in other mammalian species. Given a model like this, it would be interesting to see whether or not cognitive decline in normal aged mice correlates in any way with CSF flow through the cribriform plate. Given the lack of naturally occurring Alzheimer's mechanisms in mice, and the presence of other drainage pathways that are less impacted by age, that could go either way.

Cerebrospinal fluid drainage kinetics across the cribriform plate are reduced with aging

Continuous circulation and drainage of cerebrospinal fluid (CSF) are essential for the elimination of CSF-borne metabolic products and neuronal function. While multiple CSF drainage pathways have been identified, the significance of each to normal drainage and whether there are differential changes at CSF outflow regions in the aging brain are unclear.

Here, dynamic in vivo imaging of near infrared fluorescently-labeled albumin was used to simultaneously visualize the flow of CSF at outflow regions on the dorsal side (transcranial and -spinal) of the central nervous system. This was followed by kinetic analysis, which included the elimination rate constants for these regions. In addition, tracer distribution in ex vivo tissues were assessed, including the nasal/cribriform region, dorsal and ventral surfaces of the brain, spinal cord, cranial dura, skull base, optic and trigeminal nerves and cervical lymph nodes.

Based on the in vivo data, there was evidence of CSF elimination, as determined by the rate of clearance, from the nasal route across the cribriform plate and spinal subarachnoid space, but not from the dorsal dural regions. Using ex vivo tissue samples, the presence of tracer was confirmed in the cribriform area and olfactory regions, around pial blood vessels, spinal subarachnoid space, spinal cord and cervical lymph nodes, but not for the dorsal dura, skull base, or the other cranial nerves. Also, ex vivo tissues showed retention of tracer along brain fissures and regions associated with cisterns on the brain surfaces, but not in the brain parenchyma. Aging reduced CSF elimination across the cribriform plate but not that from the spinal SAS nor retention on the brain surfaces.

Collectively, these data show that the main CSF outflow sites were the nasal region across the cribriform plate and from the spinal regions in mice. In young adult mice, the contribution of the nasal and cribriform route to outflow was much higher than from the spinal regions. In older mice, the contribution of the nasal route to CSF outflow was reduced significantly but not for the spinal routes. This kinetic approach may have significance in determining early changes in CSF drainage in neurological disorder, age-related cognitive decline, and brain diseases.

Thymic Involution and the Decline of the Immune System with Age
https://www.fightaging.org/archives/2020/12/thymic-involution-and-the-decline-of-the-immune-system-with-age/

Thymocytes created in the bone marrow travel to the thymus, and there mature into T cells of the adaptive immune system. The thymus, unfortunately, atrophies with age, a process known as thymic involution. By age 50 it is largely fat tissue, and the supply of new T cells diminishes to a trickle. In old age, the total number of T cells remains much the same as in youth, but absent regular reinforcements, all too many of these vital cells are worn, damaged, exhausted, senescent, and often pathologically misconfigured. Too few competent T cells remain to carry out the vital tasks of killing pathogens and errant, potentially cancerous cells. This is a major cause of immune system aging and the frailty and vulnerability that follows.

The thymus, which exists in nearly all vertebrates, is a primary lymphoid organ essential for the maturation of bone marrow (BM)-derived T lymphoid precursors. The maturation and selection processes of T cells in the thymus generate a pool of circulating naïve CD4 and CD8 T cells. Such a pool allows the generation of immunity, on the one hand, and the ability to maintain tolerance to self-antigens, on the other hand. A proper thymic output may thus be considered a crucial first stage that generates a highly diverse T-cell repertoire, which is required to maintain plasticity, protection, and repair, while minimizing the risk of pathogenic autoimmunity. Since CD4 T cells evolved to play a key role in orchestrating these functions, they may be considered keystone in the ecosystem of properly regulated immunity.

Regardless of the seemingly crucial role of the thymus in preserving homeostasis, its involution begins in childhood and peaks up around puberty, resulting in an almost completely non-functional organ in aging. Thymus involution gradually reduces the output of naïve T cells with age. Dynamic changes in the thymic T lymphocytes include a reduced number of undifferentiated T cells and an increase in terminally differentiated cells (e.g., T cells with memory phenotypes). A hint to the effect of thymus involution can be found in the context of early life (before puberty) thymectomy. In young humans, thymectomy results in T-cell changes that are similar to those related to immunosenescence. Specifically, it was shown that the number of both CD4 and CD8 naïve T cells decreases while the number of memory and exhausted phenotypes increases.

These studies may imply a causal link between thymus involution and accumulating defects in the immune system with aging. The overall process that leads to immune failure in old age is apparently the sum of parallel processes, namely, thymus involution, intrinsic T-cell defects, chronic inflammation, and cell senescence. Targeting these components may shed light on the impact of each process and its therapeutic potential for the restoration of immunity and its repair in elderly.

BioAge Raises $90M and Prepares for Clinical Trials of Small Molecules to Slow Effects of Aging
https://www.fightaging.org/archives/2020/12/bioage-raises-90m-and-prepares-for-clinical-trials-of-small-molecules-to-slow-effects-of-aging/

The first wave of longevity industry companies to reach clinical trials and large funding rounds are those that focus on the well established methodology of small molecule development. Many are also platform companies that have developed approaches to speed up the expensive and time-consuming tasks of screening and designing small molecules. With the exception of the small molecule senolytics companies, these treatments presently tend to epitomize what the SENS Research Foundation folk would call "messing with metabolism," a poor alternative to actually targeting and fixing underlying causes of aging. This messing with metabolism usually means finding a molecule that can provoke cells into undertaking some of the same repair and maintenance mechanisms that occur in response to exercise, calorie restriction, heat, cold, toxins, and other stresses. The outcomes in mice are usually no better than the benefits resulting from exercise or calorie restriction.

We live in a world conditioned to expect very little from medicine to treat diseases of aging - no great surprise given that, historically, no-one tried to target the causes of aging. There is only so much you can do to keep a damaged machine running if you persist in not repairing the damage. We have a regulatory system that is geared up to the task of picking out marginally successful therapies from those that do nothing. In this world, turning up with a therapy that is 25% or 50% as good as the results of structured exercise in old people, small improvements across the board for all aspects of aging, is a real step forward from the status quo. But it is still a very poor strategy in comparison to that of the SENS program. We should be repairing the causes of aging, not tinkering with the broken metabolism of older people to try to make it a little more resilient to the burden of damage. Repair is the only way that we humans are going to gain additional decades and more of healthy life.

BioAge Labs, Inc., a biotechnology company developing medicines to treat aging and aging-related diseases, today announced that it has raised $90 million in an oversubscribed Series C financing. The raise was co-led by Andreessen Horowitz and serial entrepreneur, Elad Gil, and included new investors Kaiser Foundation Hospitals, AARP Foundation (through the RockCreek Impact Fund) and Phi-X Capital, the fund of genomics entrepreneur Mostafa Ronaghi, among others. Current investors including Caffeinated Capital, Redpoint Ventures, PEAR Ventures, AME Cloud Ventures, Felicis Ventures, and others also participated.

Proceeds from the financing will be used to build and develop a diversified portfolio of therapies that increase healthspan and lifespan, augment BioAge's artificial intelligence (AI)-driven approach to map the molecular pathways that impact human longevity, and further expand capabilities to test drug candidates in predictive models of human diseases of aging. "These additional funds will support advancement of our pipeline of medicines that target these pathways to reverse or eradicate diseases and extend healthspan. We look forward to advancing our first platform-derived therapies, BGE-117 and BGE-175 into clinical trials in the first half of 2021."

"Drugs that target aging have potential to treat several morbid diseases and improve the lives of older adults. BioAge has built a proprietary engine to analyze molecular signatures in aging populations, and to advance data-driven hypotheses to identify existing clinical-stage drugs that are ready for Phase 2 efficacy trials in age-related diseases. I'm excited to work with them as they scale their platform and develop multiple therapies to improve the health of older individuals."

How Much of Cognitive Decline is Actively Maintained via Dysfunctional Cell States or Signaling, and is thus Quickly Reversible?
https://www.fightaging.org/archives/2020/12/how-much-of-cognitive-decline-is-actively-maintained-via-dysfunctional-cell-states-or-signaling-and-is-thus-quickly-reversible/

Demonstrations in which researchers adjust cell state or signaling to reverse cognitive decline in old mice suggest that a meaningfully large fraction of this age-related cognitive decline is actively maintained via dysfunctions in cell signaling and cell activity. Senescent cells and their inflammatory signaling are a likely culprit, though it is challenging to join the dots between signaling and specific mechanisms inside cells in the highly complex environment of cellular biochemistry. The important point is that much of the decline in cognitive function could be quickly reversed if specific signals and mechanisms can be addressed. The work here is hopeful evidence on that front, though we should not forget that there remain later stages of neurodegenerative conditions in which too much damage has been done, too many cells have been lost in the brain, for there to be a solution of this nature.

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study. The drug, called integrated stress response inhibitor (ISRIB), targeting eIF2α phosphorylation, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer and even enhance cognition in healthy animals. In the new study, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

"ISRIB's extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological "blockage" rather than more permanent degradation. The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress. Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time."

GATA6 in the Mechanisms of Functional Rejuvenation of Cell Properties via Reprogramming
https://www.fightaging.org/archives/2020/12/gata6-in-the-mechanisms-of-functional-rejuvenation-of-cell-properties-via-reprogramming/

Here, researchers explore the mechanisms governing changes in cell behavior during reprogramming. Many of the aspects of aging found in cells taken from old tissues can be reversed via the process of reprogramming these cells into induced pluripotent stem cells. Mitochondrial function is restored to youthful levels, for example, as well as much of the epigenetic signature that determines protein production and cell function. There are issues that are not addressed, such as mutations, but this effect of reprogramming is sufficiently interesting to have given rise to several research programs and the company Turn.bio, seeking to build a therapy on the basis of partially reprogramming cells to the point at which rejuvenation occurs.

Scientists know that cellular reprogramming can reverse the process of cellular aging that leads to a decline in the activities and functions of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms haven't been clear. Newly reported research has identified a key role for a protein known as GATA6, in this reversal process. Researchers used cellular reprogramming to establish a genetically identical young and old cell model. They began by isolating MSCs from human synovial fluid (SF-MSCs), and reprogrammed them into induced pluripotent stem cells (iPSCs) using the Yamanaka transcription factors. Then they differentiated these iPSCs back to MSCs, in effect rejuvenating the MSCs.

The scientists next conducted an analysis of the cells to determine if there were any changes in global gene expression resulting from the reprogramming. They found that the expression of GATA6, a protein that plays an important role in gut, lung, and heart development, was repressed in the reprogrammed cells compared with the control cells. This repression led to increased activity of a protein called sonic hedgehog (SHH) that is essential to embryonic development, as well as the expression level of another protein, FOXP1, which is necessary for proper development of the brain, heart, and lung.

To determine which of the Yamanaka transcription factors were involved in repressing GATA6 in the iPSCs, the team analyzed GATA6 expression in response to the knockdown of each factor. The results indicated that only OCT4 and KLF4 were able to regulate GATA6 activity, a finding that is consistent with that of several previous studies.

The Connected Age-Related Atrophy of Thymus and Pineal Gland
https://www.fightaging.org/archives/2020/12/the-connected-age-related-atrophy-of-thymus-and-pineal-gland/

Decades ago, the pineal gland was the focus of a great deal of ignorant hype regarding research into aging and the prospects for treating aging. The paper here is an interesting overview of what is known about possible connections between the thymus and the pineal gland, both of which atrophy with age, and both of which have sweeping effects on the immune system. It is perhaps of greatest interest as a catalog of things yet to be discovered - roads leading into the dark forest from the starting point of lists of molecules secreted by thymus and pineal gland, added to what is known of what goes on inside these two organs, and what those molecules are known to do elsewhere in the body. There is the suspicion that some of these roads may cross somewhere in the great expanse of metabolism that is yet to be well mapped, but a much work has yet to be accomplished in order to find out whether or not this is the case.

Mutual influences and bidirectional networks among the nervous system, endocrine system, and immune systems are mediated by hormones, cytokines/chemokines and their binding sites, contributing, in turn, to body homeostasis. Many interactions are mediated by the highly regulated release of several hormones and peptides into the vessels, which have direct effects on the immune system. In particular, many studies have reported interactions between the pineal gland (PG), thymus gland (TG), and other parts of the immune system owing to the widespread expression of receptors that detect the respective humoral signals.

The impairment of TG and PG functions, mainly related to neuroendocrine and immune systems, is associated with ageing, and unfortunately, the physiological deterioration is a precursor to pathologies. Moreover, the alterations of the TG-PG axis during ageing are already indicative of a close relationship between these two glands. In fact, the PG, certainly via melatonin, but perhaps also via additional factors such as thyroid-stimulating hormone (TSH) and other peptides, influences humoral and cellular immunity, immune cell proliferation and immune mediator production. The TG is central to many immunological functions, which are mediated by peptides. Moreover, these glands play an important role as a functional unit because they constitute a bidirectional system in which PG acts on TG and vice versa. Thus, they have a mutual complementarity in the maintenance of a normal immune and endocrine status, which becomes especially evident in ageing.

Researchers have reported an influence of thymic peptides on PG and pineal peptides on TG. Importantly, removal of the PG induces decreases in thymus weight, the number of thymic cells, and TG secretory functions. The blockage of PG, induced by pharmacological treatments, also resulted in a decrease of the thymic hormone, thymulin, in the blood. Moreover, thymectomy caused changes in biorhythms for several immune indicators of glucocorticoid synthesis by the adrenal cortex. The bidirectional communication between TG and PG is also due to the release of some cytokines that are secreted by these glands. One of them is tumour necrosis factor-α (TNF-α) which is produced, apart from other immune cells, in the thymic medulla.

According to our current knowledge, the mutual functional relationship of the TG-PG axis during the phases of life and, particularly, in ageing would benefit from and be worth of increasing research efforts. To date, the literature is still somewhat scanty and does not easily reveal the entire complexity of their relationships, in part because many findings are relatively old and often published in languages rarely used in science. The histological and functional losses of both the PG and TG are salient features of ageing. The message of this article is that they seem to be interrelated.

IL-6 Contributes to Age-Related Loss of Mitochondrial Function in Cerebral Vasculature
https://www.fightaging.org/archives/2020/12/il-6-contributes-to-age-related-loss-of-mitochondrial-function-in-cerebral-vasculature/

Chronic inflammation grows with age throughout the body, characterized by increased levels of numerous inflammatory signal molecules, among which is IL-6. One contributing factor to the chronic inflammation of aging is the accumulation of lingering senescent cells, which rouse the immune system via secreted molecules that include, prominently, IL-6. Researchers here home in on one narrow consequence of this changed environment, finding that IL-6 signaling in cerebral vasculature impairs mitochondrial function and the maintenance process of mitophagy responsible for clearing out damaged mitochondria. Loss of mitochondrial function is, in general, a feature of aging, and implicated in many age-related conditions. It is interesting to see an example of a very direct connection between the presence of senescent cells, now well established as a cause of aging, and age-related mitochondrial dysfunction.

The blood-brain barrier (BBB) is critical for cerebrovascular health. Although aging impairs the integrity of the BBB, the mechanisms behind this phenomenon are not clear. As mitochondrial components activate inflammation as mitochondria become dysfunctional, we examined how aging impacts cerebrovascular mitochondrial function, mitophagy, and inflammatory signaling; and whether any alterations correlate with BBB function.

We isolated cerebral vessels from young (2-3 months of age) and aged (18-19 months of age) mice and found that aging led to increases in the cyclin-dependent kinase inhibitor 1 senescence marker with impaired mitochondrial function, which correlated with aged mice exhibiting increased BBB leak compared with young mice. Cerebral vessels also exhibited increased expression of mitophagy proteins Parkin and Nix with aging. Using mitophagy reporter (mtKeima) mice, we found that the capacity to increase mitophagy from baseline within the cerebral vessels on rotenone treatment was reduced with aging. Aging within the cerebral vessels also led to the upregulation of the stimulator of interferon genes and increased interleukin 6 (IL-6), a cytokine that alters mitochondrial function.

Importantly, exogenous IL-6 treatment of young cerebral vessels upregulated mitophagy and Parkin and impaired mitochondrial function; whereas inhibiting IL-6 in aged cerebral vessels reduced Parkin expression and increased mitochondrial function. Furthermore, treating cerebral vessels of young mice with mitochondrial N-formyl peptides upregulated IL-6, increased Parkin, and reduced Claudin-5, a tight junction protein integral to BBB integrity. In conclusion, aging alters the cerebral vasculature to impair mitochondrial function and mitophagy and increase IL-6 levels. These alterations may impair BBB integrity and potentially reduce cerebrovascular health with aging.

Senescent Cells Fail to Maintain Proteostasis
https://www.fightaging.org/archives/2020/12/senescent-cells-fail-to-maintain-proteostasis/

Given the newfound consensus in the research community regarding the importance of senescent cells to degenerative aging, it isn't surprising to see a great deal more fundamental research into the biochemistry of cellular senescence now taking place than was previously the case. In many cases it isn't all that clear as to whether an incrementally greater understanding of mechanism A or mechanism B will at any point be helpful to the development of senolytic therapies to selectively destroy senescent cells, but that is the way of fundamental research. It is hard to say in advance what will turn out to be a big deal at the end of the day.

Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence.

Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature.

Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

An Interview with Alex Zhavoronkov of Insilico Medicine
https://www.fightaging.org/archives/2020/12/an-interview-with-alex-zhavoronkov-of-insilico-medicine/

Alex Zhavoronkov founded Insilico Medicine, an early company in the young longevity industry, and the first of many to focus on machine learning as a way to improve research infrastructure in drug discovery. Here he offers a selection of opinions on the longevity industry, the approaches he thinks are most interesting. It is worth bearing in mind that his bias is very much towards the use of machine learning and small molecule therapeutics, which is far from a full list of everything that is taking place.

Can you give our listeners a quick overview of the longevity and aging field.

It will be difficult to make a short intro into the longevity industry because it is broad and encompasses many fields that also relate to general biotechnology, pharmaceutical, and healthcare. I would define longevity medicine as a field of AI powered preventative medicine focused on biomarkers of aging. Recently, the longevity industry has advanced quite dramatically. Just in the last ten years, we have seen convergences that integrate soft sciences like information technology with biotechnology. This union resulted in the discovery and rapid adoption of a technology called aging clocks or biomarkers of aging.

Aging clocks were originally developed on methylation data, so epigenetic data by Steve Horvath and the Hannum group from 2011-2013. Our group picked up the trend and converged it with artificial intelligence and developed a range of deep biomarkers of aging or deep aging clocks. We have a variety of aging clocks built on blood tests, transcriptomic data, proteomic data, methylation data and aging data. Pretty much any data that changes in time. This allows us to tangibly measure aging. I believe that this introduction will be the next-generation of the longevity industry.

How about the therapeutic side? What are some drug candidates targeting aging?

I like to break therapeutics down into 5 areas. 1) Rapalogs, derivatives or analogues of rapamycin. 2) Senolytics, drugs that target senescent cells and allow for cells to be replenished, to be recycled. 3) NAD boosters. Multiple groups worldwide discovered that elevating the level of NAD+ molecule at the cellular level results in increases in health and lifespan in model organisms. 4) Metformin, an old diabetic and pre-diabetic drug and now people of all ages are also taking it for longevity. There is a clinical trial on the way called TAME that targets aging. 5) Alpha-ketogluterate (or AKG). AKG is off patent and thus difficult to get intellectual property protection, but it looks like it holds a lot of promise in aging and age-related diseases as well.

What are your expectations for the aging field in the next decade?

We are starting to see companies and even clinical centres combining diagnostics and therapeutics. Unfortunately, we do not see this industry being perceived as credible by the insurance industry and by large pharmaceutic industries, yet at least. We're getting there but we still have a long way to go. I think that in general, the longevity industry is pretty early in its development, so we don't see the hype in longevity yet. We do see venture capital industry members getting into the field. They are funding all kinds of projects, credible and uncredible, and it is great. This investment reminds me of the social networking era, or the era of computing where people were betting on all kinds of projects during the dotcom boom. I think that we are going to see a major boom in aging within the next decade or two. So, if you are a young pharmaceutical executive or if you are a medical student, I would take this industry as a priority for career development.

Analysis of Human Inheritance of Longevity is not as Straightforward as One Might Think
https://www.fightaging.org/archives/2020/12/analysis-of-human-inheritance-of-longevity-is-not-as-straightforward-as-one-might-think/

Here, researchers note some of the challenges inherent in trying to analyze data on human inheritance of longevity; it isn't as easy as it sounds. Considerable effort has gone into analysis of long-lived families to try to identify genetic variants that might explain why some lineages exhibit greater longevity than others. Nonetheless, so far only a small number of gene variants have been robustly demonstrated to influence human longevity. This poor yield is not for lack of searching, but because it seems likely that individual genetic contributions to longevity are both very small and very specific to environmental circumstances. Every study finds novel variants that correlate within that study population, but no other study is able to replicate that finding. This ultimately leads to a growing consensus that familial longevity is more a matter of transmission of culture and environment than transmission of genes: exercise, diet, exposure to persistent pathogens, and so forth.

The study of such exceptionally old individuals (longevity) is important as they likely harbor gene-environment interactions which beneficially regulate the molecular pathways involved in longevity, resistance to disease, resilience to negative side-effects of treatment and therefore healthy aging. It has been estimated that age at death (lifespan) attributes for ~25% to genetic variation and this number rises for long-lived individuals as shown by its strong familial clustering. Nevertheless, two decades of genetic research to understand the mechanisms of longevity and healthy aging had limited robust results. Amongst a number of potential determinants, only the APOE and FOXO3A genes have been consistently identified.

One of the main reasons for the difficulty of identifying genes promoting longevity and healthy aging is the lack of a consistent definition for heritable longevity, which resulted in a mix of sporadically long-lived cases with those descending from a long-lived family and a large variation of longevity definitions used in longevity research. The presence of sporadically long-lived cases is illustrated by the increase of centenarians in the United States between 1994 and 2012 from 1 in 10,000 to 2 in 10,000. Secondly, Genome Wide Association (GWA) analysis, the leading method in complex disease mapping, relies on comparing living long-lived individuals (cases) with averagely living individuals (controls). These averagely lived individuals can in fact become long-lived over time, thus potentially confusing cases and controls.

In addition, recent research revealed the importance of rare and structural variants in addition to the common single nucleotide polymorphisms (SNPs) studied in GWAS. Thirdly, socio-behavioral and environmental factors, such as lifestyle, socioeconomic status, social network, and the living environment shaped the aging process of long-lived persons in interaction with their genes. However, these factors are rarely included in genetic longevity studies and surprisingly little is known about how they cluster in long-lived families.

The issue of unintentionally including sporadically long-lived cases has recently been addressed in two studies, using multiple large scale family tree databases; the Utah Population Database (UPDB), the LINKing System for historical family reconstruction (LINKS), and the Historical Sample of the Netherlands Long Lives (HSN-LL) which contain thousands of families. The studies showed that longevity is only transmitted across generations if at least 30% of the ancestors of a person belonged to the top 10% survivors of their birth cohort and the persons themselves also belong to the 10% longest lived. Importantly, 27% of the HSN-LL research persons showed a survival pattern similar to the general population even though they had at least one long-lived parent. Based on these results, the Longevity Relatives Count (LRC) score was developed as an instrument to identify genetically enriched long-lived persons for case inclusion in genetic studies and thus avoid the inclusion of sporadically long-lived persons.

HAND2 Overexpression in Sympathetic Neurons Slows the Onset of Sarcopenia in Aged Mice
https://www.fightaging.org/archives/2020/12/hand2-overexpression-in-sympathetic-neurons-slows-the-onset-of-sarcopenia-in-aged-mice/

Researchers here show that upregulation of HAND2 in sympathetic neurons has the effect of slowing sarcopenia in late life, the loss of muscle mass and strength that leads to frailty. One contributing cause of sarcopenia is the deterioration of the neuromuscular junctions that link the nervous system with muscle tissue. This approach slows that deterioration, with a corresponding slowing of loss of muscle function, and thus puts some numbers to the importance of that causes versus, say, loss of stem cell function.

Sarcopenia, or age-dependent decline in muscle force and power, impairs mobility, increasing the risk of falls, institutionalization, co-morbidity, and premature death. The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system (SNS) neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle-wasting conditions. Interventions that can adjust neurotransmitter release to changing physiological demands depend on understanding how the SNS affects neuromuscular transmission, muscle motor innervation, and muscle mass.

We examined age-dependent expression of the heart and neural crest derivative 2 (Hand2), a critical transcription factor for SN maintenance, and we tested the possibility that inducing its expression exclusively in sympathetic neurons (SN) will prevent (i) motor denervation, (ii) impaired neuromuscular junction (NMJ) transmission, and (iii) loss of muscle mass and function in old mice. To test this hypothesis, we delivered a viral vector carrying Hand2 expression or an empty vector exclusively in SNs by vein injection in 16-month-old C57BL/6 mice that were sacrificed 6 months later.

Hand2 expression declines throughout life, but inducing its expression increased (i) the number and size of SNs, (ii) muscle sympathetic innervation, (iii) muscle weight and force and whole-body strength, (iv) myofiber size but not muscle fibre-type composition, (v) NMJ transmission and nerve-evoked muscle force, and (vi) motor innervation in old mice. Additionally, the SN controls a set of genes to reduce inflammation and to promote transcription factor activity, cell signalling, and synapse in the skeletal muscle. Hand2 DNA methylation may contribute, at least partially, to gene silencing.

Further, selective expression of Hand2 in the mouse SNs from middle age through old age increases muscle mass and force by (i) regulating skeletal muscle sympathetic and motor innervation; (ii) improving acetylcholine receptor stability and NMJ transmission; (iii) preventing inflammation and myofibrillar protein degradation; (iv) increasing autophagy; and (v) probably enhancing protein synthesis.