Fight Aging! Newsletter, December 14th 2020

Posted on: December 13, 2020

Fight Aging! Newsletter, December 14th 2020

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  • 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

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

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

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.

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

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."

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