Are you over 18 and want to see adult content?
More Annotations
A complete backup of https://ibcbettas.org
Are you over 18 and want to see adult content?
A complete backup of https://pfrf-kabinet.ru
Are you over 18 and want to see adult content?
A complete backup of https://nodeknockout.com
Are you over 18 and want to see adult content?
A complete backup of https://signal.bg
Are you over 18 and want to see adult content?
A complete backup of https://kidblog.org
Are you over 18 and want to see adult content?
A complete backup of https://asinupress.com
Are you over 18 and want to see adult content?
A complete backup of https://environmental-expert.com
Are you over 18 and want to see adult content?
A complete backup of https://pharmacy-prices-canada.com
Are you over 18 and want to see adult content?
A complete backup of https://chivmen.com
Are you over 18 and want to see adult content?
A complete backup of https://lightedge.com
Are you over 18 and want to see adult content?
A complete backup of https://globalfitcommunity.com
Are you over 18 and want to see adult content?
A complete backup of https://ludothequelancy.ch
Are you over 18 and want to see adult content?
Favourite Annotations
A complete backup of jenniferashley.com
Are you over 18 and want to see adult content?
A complete backup of fortnitedicas.com.br
Are you over 18 and want to see adult content?
A complete backup of mastercril.com.br
Are you over 18 and want to see adult content?
A complete backup of linkneverdie.vip
Are you over 18 and want to see adult content?
A complete backup of caballo-indomable.blogspot.com
Are you over 18 and want to see adult content?
A complete backup of getapologyletter.com
Are you over 18 and want to see adult content?
A complete backup of frizzyhub.com.ng
Are you over 18 and want to see adult content?
A complete backup of hwcollectorsnews.com
Are you over 18 and want to see adult content?
Text
FIGHT AGING!
Aggregation of amyloid-β is a feature of the slow buildup towards Alzheimer's disease that takes place in later life, though it remains unclear as to whether this protein aggregation is a cause or a side-effect in the progression of the condition. Separately, loss of capillary density is a feature of aging in tissues throughout the body. In energy-hungry tissues such as the brain, this is a ADUCANUMAB APPROVED BY FDA TO TREAT ALZHEIMER’S DISEASE Aducanumab Approved by FDA to Treat Alzheimer's Disease. The underside of the approval of aducanumab, an immunotherapy that clears amyloid-β from the brain, is very much a textbook case of regulatory capture. While the treatment does clear amyloid-β, it doesn't help patients all that much. Benefits observed in trials were marginal to the THE FUTURE OF HUMAN LONGEVITY WILL BE VERY DIFFERENT FROM The Future of Human Longevity will be Very Different from the Past. Human life expectancy has increased through two distinct process; firstly a reduction in child mortality, and second a reduction in the burden of damage accumulated over an adult life span. Control of infectious disease has played a large role in both components of gainsin
DIGGING DEEPER INTO THE MECHANISMS OF CALORIE RESTRICTION Calorie restriction promotes longevity, slowing the progression aging via sweeping metabolic changes across an entire organism. The metabolic changes it produces in cells are very similar in all species studied to date. This is one of the reasons why calorie restriction is so well studied: one can carry out low-cost experiments in yeast andnonetheless
TOWARDS BETTER SCAFFOLDS FOR MUSCLE REGENERATION Building better scaffolding materials for tissue regrowth is one important line of work in the regenerative medicine.The idea is to better mimic necessary characteristics of the natural extracellular matrix, to make the cells inhabiting the scaffold material behave in ways that are conducive to regrowth and regeneration.The open access paper noted here is an example of this sort of ongoing FOUR SUBTYPES OF ALZHEIMER’S DISEASE BASED ON DIFFERING Researchers have recently proposed a taxonomy of subtypes of Alzheimer's disease based on differences in the spread of tau protein aggregation through the brain that is characteristic of the later stages of the condition. Tau aggregation caused dysfunction and cell death in neurons.It is interesting to speculate as to the underlying reasons why there are four such classes of progression of tau THE PRESENT UNDERSTANDING OF THE RELATIONSHIP BETWEEN The Present Understanding of the Relationship Between Growth Hormone and Longevity. Growth hormone treatments (and other hormone therapies) have a legitimate use in patients suffering excessively low hormone levels due to one or another cause. They have also long been overhyped and aggressively marketed by the anti-aging medicine community, not OVERHYPING THE EFFECTS OF HYPERBARIC OXYGEN TREATMENT ON An interesting open access paper was recently published on the effects of hyperbaric oxygen treatment on telomere length and cellular senescence in immune cells taken from blood samples. I use the word "interesting" quite deliberately, because that is exactly and all that this research is. The paper is appropriately formal and modest on thatfront,
AN OVERVIEW OF COMPANIES TARGETING MITOCHONDRIAL Today's materials are a helpful overview of the brace of biotech companies working to slow or reverse aspects of mitochondrial aging. Mitochondria play a central role in core cellular processes and are important in degenerative aging. Every cell contains a herd of hundreds of mitochondria, the descendants of an ancient symbiosis between the first cells A DISCUSSION OF EPIGENETIC REPROGRAMMING AND A Discussion of Epigenetic Reprogramming and Rejuvenation. Cell reprogramming can be achieved by gene therapies that express pluripotency genes - some or all of the Yamanaka factors. It is akin to the process that takes place in the early stages of embryonic development, and which removes the mitochondrial dysfunction and epigenetic alterationsFIGHT AGING!
Aggregation of amyloid-β is a feature of the slow buildup towards Alzheimer's disease that takes place in later life, though it remains unclear as to whether this protein aggregation is a cause or a side-effect in the progression of the condition. Separately, loss of capillary density is a feature of aging in tissues throughout the body. In energy-hungry tissues such as the brain, this is a ADUCANUMAB APPROVED BY FDA TO TREAT ALZHEIMER’S DISEASE Aducanumab Approved by FDA to Treat Alzheimer's Disease. The underside of the approval of aducanumab, an immunotherapy that clears amyloid-β from the brain, is very much a textbook case of regulatory capture. While the treatment does clear amyloid-β, it doesn't help patients all that much. Benefits observed in trials were marginal to the THE FUTURE OF HUMAN LONGEVITY WILL BE VERY DIFFERENT FROM The Future of Human Longevity will be Very Different from the Past. Human life expectancy has increased through two distinct process; firstly a reduction in child mortality, and second a reduction in the burden of damage accumulated over an adult life span. Control of infectious disease has played a large role in both components of gainsin
DIGGING DEEPER INTO THE MECHANISMS OF CALORIE RESTRICTION Calorie restriction promotes longevity, slowing the progression aging via sweeping metabolic changes across an entire organism. The metabolic changes it produces in cells are very similar in all species studied to date. This is one of the reasons why calorie restriction is so well studied: one can carry out low-cost experiments in yeast andnonetheless
TOWARDS BETTER SCAFFOLDS FOR MUSCLE REGENERATION Building better scaffolding materials for tissue regrowth is one important line of work in the regenerative medicine.The idea is to better mimic necessary characteristics of the natural extracellular matrix, to make the cells inhabiting the scaffold material behave in ways that are conducive to regrowth and regeneration.The open access paper noted here is an example of this sort of ongoing FOUR SUBTYPES OF ALZHEIMER’S DISEASE BASED ON DIFFERING Researchers have recently proposed a taxonomy of subtypes of Alzheimer's disease based on differences in the spread of tau protein aggregation through the brain that is characteristic of the later stages of the condition. Tau aggregation caused dysfunction and cell death in neurons.It is interesting to speculate as to the underlying reasons why there are four such classes of progression of tau THE PRESENT UNDERSTANDING OF THE RELATIONSHIP BETWEEN The Present Understanding of the Relationship Between Growth Hormone and Longevity. Growth hormone treatments (and other hormone therapies) have a legitimate use in patients suffering excessively low hormone levels due to one or another cause. They have also long been overhyped and aggressively marketed by the anti-aging medicine community, not OVERHYPING THE EFFECTS OF HYPERBARIC OXYGEN TREATMENT ON An interesting open access paper was recently published on the effects of hyperbaric oxygen treatment on telomere length and cellular senescence in immune cells taken from blood samples. I use the word "interesting" quite deliberately, because that is exactly and all that this research is. The paper is appropriately formal and modest on thatfront,
AN OVERVIEW OF COMPANIES TARGETING MITOCHONDRIAL Today's materials are a helpful overview of the brace of biotech companies working to slow or reverse aspects of mitochondrial aging. Mitochondria play a central role in core cellular processes and are important in degenerative aging. Every cell contains a herd of hundreds of mitochondria, the descendants of an ancient symbiosis between the first cells A DISCUSSION OF EPIGENETIC REPROGRAMMING AND A Discussion of Epigenetic Reprogramming and Rejuvenation. Cell reprogramming can be achieved by gene therapies that express pluripotency genes - some or all of the Yamanaka factors. It is akin to the process that takes place in the early stages of embryonic development, and which removes the mitochondrial dysfunction and epigenetic alterations THE MAINSTREAM MEDIA IS SLOWLY BECOMING LESS SKEPTICAL OF 5 hours ago · 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 TRENDS IN HUMAN HEALTHSPAN VERSUS LIFESPAN Aging is damage, and the body fails in the same way that any complex, damaged machine fails.If one slows the pace of damage accumulation, as technological progress over the past century has achieved to a modest degree, albeit by accident rather than intent, both overall life span and the time spent in a period of damage and dysfunction at the end oflife should extend.
ATHLETES UNDERGOING REGULAR STRENGTH TRAINING EXHIBIT 5 hours ago · 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 TARGETING SENESCENT CELLS TO REVERSE THE AGING OF THE Senescent cells accumulate with age and cause a wide range of pathologies. They contribute in some way to near all of the common, ultimately fatal age-related conditions. Senescent cells secrete a mix of signals that produces chronic inflammation, disrupts tissue maintenance to encourage fibrosis, and changes the behavior of other cells for the worse in CD4 / CD8 T CELL RATIO AS A MEASURE OF IMMUNE AGING The state of the aged adaptive immune system can be assessed in a practical way in animal studies, such as via exposure to influenza or other well-calibrated infectious disease. This assessment is also carried out on the human population as a whole in every influenza season, but for individual humans one wants a metric that is a littleless do or die.
THE PRESENT UNDERSTANDING OF THE RELATIONSHIP BETWEEN The Present Understanding of the Relationship Between Growth Hormone and Longevity. Growth hormone treatments (and other hormone therapies) have a legitimate use in patients suffering excessively low hormone levels due to one or another cause. They have also long been overhyped and aggressively marketed by the anti-aging medicine community, not ASSESSING SARCOPENIA AND DYNAPENIA VIA ULTRASOUND 1 day ago · Researchers here propose an approach to measure the progression of sarcopenia, the loss of muscle mass and strength with aging, via ultrasound assessment of muscle structure. The present most widely practiced approaches involve assessment of muscle mass, grip strength, walking speed, ability to stand up from a chair, and the like. As understanding of the THERE IS NO ONE UNIVERSAL PRO-LONGEVITY GUT MICROBIOME Evidence suggests that the gut microbiome is influential on long-term health and late life mortality, to perhaps a similar degree as exercise. The various populations of microbial life found in the gut change with age; microbes producing beneficial metabolites are lost, while microbes that provoke chronic inflammation or other issues increase in number. Experiments in AN EXAMPLE OF HIGH DOSE FISETIN EXHIBITING SENOLYTIC An Example of High Dose Fisetin Exhibiting Senolytic Effects in Mice. Fisetin is perhaps the most intriguing of the first generation senolytic compounds, those capable of selectively destroying senescent cells in old tissues and thus producing rejuvenation to a meaningful degree. Senolytics have been demonstrated in animal studies to reverse TH17 IMMUNITY AND THE INFLAMMATION OF AGING IN INTESTINAL 1 day ago · The immune system is a very complex network of many different cell types, signals, and layered responses. It is much more subdivided and varied than the broad distinction between innate and adaptive immune components might lead one to believe. As a whole the immune system runs awry in later life, becoming both overly active and incompetent at the same time.FIGHT AGING!
The state of the aged adaptive immune system can be assessed in a practical way in animal studies, such as via exposure to influenza or other well-calibrated infectious disease. This assessment is also carried out on the human population as a whole in every influenza season, but for individual humans one wants a metric that is a littleless do or die.
TARGETING SENESCENT CELLS TO REVERSE THE AGING OF THE Senescent cells accumulate with age and cause a wide range of pathologies. They contribute in some way to near all of the common, ultimately fatal age-related conditions. Senescent cells secrete a mix of signals that produces chronic inflammation, disrupts tissue maintenance to encourage fibrosis, and changes the behavior of other cells for the worse in INVARIANT NATURAL KILLER T CELLS CAN BE PROVOKED INTO Researchers here use the properties of a subset of natural killer T cells of the immune system in order to provoke these cells into greater activity without rousing the rest of the immune system into action. The outcome is that the activated natural killer T cells then destroy more senescent cells than would otherwise have been the case. Destroying senescent cells by any means leads to a dose CALICO, AS EXPECTED, IS WORKING ON LOW YIELD PROJECTS IN AGING Calico, As Expected, is Working on Low Yield Projects in Aging. Calico represents a sizable investment in research and development related to aging and age-related disease. Unfortunately, all the signs have pointed towards this effort going into projects that cannot possibly do more than very modestly affect aging. PROFILES OF TWO SENOLYTICS COMPANIES WITH QUITE DIFFERENT The two senolytics companies profiled here employ quite different approaches to the selective destruction of senescent cells, and indeed also to the business side of the equation - which age-related conditions to tackle first, whether to build a therapy or a platform for therapies, and so forth.These are two representative companies of a much larger number of groups working in this part of the INHIBITION OF EN1 ACTIVITY HEALS SKIN INJURIES WITHOUT There is an interesting history of accidental discoveries regarding exceptional regeneration in mammals, such as the MRL mice that are capable of regenerating the ear tags and notches that researchers use to track mice through experiments, thereby causing some confusion. Researchers have since then spent time on attempts to identify important mechanisms by which mammalian SELPHAGY THERAPEUTICS WORKS ON LAMP2A UPREGULATION TO Selphagy Therapeutics Works on LAMP2A Upregulation to Promote Autophagy. It has been more than a decade since researchers demonstrated that genetic engineering of mice to boost LAMP2A levels in the liver produced a sizable rejuvenation of liver function in old animals. This happens because increased levels of LAMP2A cause anupregulation of
NEW EVIDENCE FOR ADULT NEUROGENESIS TO OCCUR EVEN IN LATE Neurogenesis is the process by which new neurons are created in the brain and integrated into neural circuits. It is a part of the plasticity that allows for cognitive function and maintenance of that function in the face of damage. Obviously, this is a very important topic for those groups seeking ways to apply regenerative medicine tothe brain.
REVERSING HAIR GRAYNESS BY SUPPRESSING OXIDATIVE STRESS Reversing Hair Grayness By Suppressing Oxidative Stress. The graying of hair with increasing age is an early sign of increased oxidative stress in skin tissues around hair follicles. Researchers here demonstrate that it can be locally reversed by an antioxidant-based strategy. This shouldn't be taken to indicate that antioxidants are ofgeneral
EVEN EARLY STAGE KIDNEY DISEASE CAUSES COGNITIVE Even Early Stage Kidney Disease Causes Cognitive Impairment. The link between age-related kidney dysfunction and cognitive impairment is an interesting one, particularly in the context of research into klotho, which has functions in both the kidney and the brain, and has been shown to extend life and improve cognitive function in animal studies.FIGHT AGING!
The state of the aged adaptive immune system can be assessed in a practical way in animal studies, such as via exposure to influenza or other well-calibrated infectious disease. This assessment is also carried out on the human population as a whole in every influenza season, but for individual humans one wants a metric that is a littleless do or die.
TARGETING SENESCENT CELLS TO REVERSE THE AGING OF THE Senescent cells accumulate with age and cause a wide range of pathologies. They contribute in some way to near all of the common, ultimately fatal age-related conditions. Senescent cells secrete a mix of signals that produces chronic inflammation, disrupts tissue maintenance to encourage fibrosis, and changes the behavior of other cells for the worse in INVARIANT NATURAL KILLER T CELLS CAN BE PROVOKED INTO Researchers here use the properties of a subset of natural killer T cells of the immune system in order to provoke these cells into greater activity without rousing the rest of the immune system into action. The outcome is that the activated natural killer T cells then destroy more senescent cells than would otherwise have been the case. Destroying senescent cells by any means leads to a dose CALICO, AS EXPECTED, IS WORKING ON LOW YIELD PROJECTS IN AGING Calico, As Expected, is Working on Low Yield Projects in Aging. Calico represents a sizable investment in research and development related to aging and age-related disease. Unfortunately, all the signs have pointed towards this effort going into projects that cannot possibly do more than very modestly affect aging. PROFILES OF TWO SENOLYTICS COMPANIES WITH QUITE DIFFERENT The two senolytics companies profiled here employ quite different approaches to the selective destruction of senescent cells, and indeed also to the business side of the equation - which age-related conditions to tackle first, whether to build a therapy or a platform for therapies, and so forth.These are two representative companies of a much larger number of groups working in this part of the INHIBITION OF EN1 ACTIVITY HEALS SKIN INJURIES WITHOUT There is an interesting history of accidental discoveries regarding exceptional regeneration in mammals, such as the MRL mice that are capable of regenerating the ear tags and notches that researchers use to track mice through experiments, thereby causing some confusion. Researchers have since then spent time on attempts to identify important mechanisms by which mammalian SELPHAGY THERAPEUTICS WORKS ON LAMP2A UPREGULATION TO Selphagy Therapeutics Works on LAMP2A Upregulation to Promote Autophagy. It has been more than a decade since researchers demonstrated that genetic engineering of mice to boost LAMP2A levels in the liver produced a sizable rejuvenation of liver function in old animals. This happens because increased levels of LAMP2A cause anupregulation of
NEW EVIDENCE FOR ADULT NEUROGENESIS TO OCCUR EVEN IN LATE Neurogenesis is the process by which new neurons are created in the brain and integrated into neural circuits. It is a part of the plasticity that allows for cognitive function and maintenance of that function in the face of damage. Obviously, this is a very important topic for those groups seeking ways to apply regenerative medicine tothe brain.
REVERSING HAIR GRAYNESS BY SUPPRESSING OXIDATIVE STRESS Reversing Hair Grayness By Suppressing Oxidative Stress. The graying of hair with increasing age is an early sign of increased oxidative stress in skin tissues around hair follicles. Researchers here demonstrate that it can be locally reversed by an antioxidant-based strategy. This shouldn't be taken to indicate that antioxidants are ofgeneral
EVEN EARLY STAGE KIDNEY DISEASE CAUSES COGNITIVE Even Early Stage Kidney Disease Causes Cognitive Impairment. The link between age-related kidney dysfunction and cognitive impairment is an interesting one, particularly in the context of research into klotho, which has functions in both the kidney and the brain, and has been shown to extend life and improve cognitive function in animal studies. INFLAMMAGING AND DISRUPTION OF COAGULATION AS The burden of infectious disease falls most heavily upon the old. The attention given to COVID-19 has highlighted that point, though much of the media seems determined to avoid talking about the fact that near all mortality due to the condition occurs in the old and the cormorbid.It is nothing new, of course. Influenza kills tens of thousands of old people every year in the US alone, without THERE IS NO ONE UNIVERSAL PRO-LONGEVITY GUT MICROBIOME Evidence suggests that the gut microbiome is influential on long-term health and late life mortality, to perhaps a similar degree as exercise. The various populations of microbial life found in the gut change with age; microbes producing beneficial metabolites are lost, while microbes that provoke chronic inflammation or other issues increase in number. Experiments in ADUCANUMAB APPROVED BY FDA TO TREAT ALZHEIMER’S DISEASE 1 day ago · The underside of the approval of aducanumab, an immunotherapy that clears amyloid-β from the brain, is very much a textbook case of regulatory capture. While the treatment does clear amyloid-β, it doesn't help patients all that much. Benefits observed in trials were marginal to the point of non-existence. The arm-wrestling under the hood has nothing 30% TO 40% OF DEMENTIA MIGHT BE AVOIDED VIA 30% to 40% of Dementia Might be Avoided via Lifestyle Choices. Today's open access research materials present a statistical exercise that uses broad epidemiological data to determine the impact of individual lifestyle choices and environmental factors to the incidence of dementia. The results are not declaring that, say, particulate air CD4 / CD8 T CELL RATIO AS A MEASURE OF IMMUNE AGING The state of the aged adaptive immune system can be assessed in a practical way in animal studies, such as via exposure to influenza or other well-calibrated infectious disease. This assessment is also carried out on the human population as a whole in every influenza season, but for individual humans one wants a metric that is a littleless do or die.
A TREATMENT TO REBUILD TOOTH ENAMEL 1 day ago · Rebuilding lost tooth enamel is an important goal in a world in which robust control over the bacteria responsible for producing cavities has not yet been achieved.In a welcome advance in this part of the field, researchers will soon conduct trials of a low cost approach to achieve reconstruction of enamel, slowly over time. DISTINCTIVE MACROPHAGE SIGNALING IS VITAL TO AXOLOTL LIMB 14 hours ago · Research into the comparative biology of regeneration suggests that mammals are in principle capable of proficient, full regeneration of complex tissues, but some critical difference in cell signaling and behavior leads instead to the formation of scar tissue in adults. In recent years, scientists have focused on the role of macrophages in coordinating the process INHIBITION OF EN1 ACTIVITY HEALS SKIN INJURIES WITHOUT There is an interesting history of accidental discoveries regarding exceptional regeneration in mammals, such as the MRL mice that are capable of regenerating the ear tags and notches that researchers use to track mice through experiments, thereby causing some confusion. Researchers have since then spent time on attempts to identify important mechanisms by which mammalian AN EXAMPLE OF HIGH DOSE FISETIN EXHIBITING SENOLYTIC An Example of High Dose Fisetin Exhibiting Senolytic Effects in Mice. Fisetin is perhaps the most intriguing of the first generation senolytic compounds, those capable of selectively destroying senescent cells in old tissues and thus producing rejuvenation to a meaningful degree. Senolytics have been demonstrated in animal studies to reverse A LESS WELL EXPLORED CDKN1A TRANSCRIPT IS A MARKER OF 14 hours ago · The gene Cdkn1a (or P21) generates two different RNA transcripts that both lead to the production of the same protein. Researchers here provide evidence to suggest that the less well explored second transcript is a good marker of aging and cellular senescence, at least in mice.The biochemistry of senescence seems to be well conserved across species, so with luck the same data will be__ __
* Home __
* FAQ __
* Fund Research __
* Services __
* Investing __
* Therapies __
* Newsletter __
* Archives __
* Press Room __
* Resources __
* About __
FIGHT AGING!
Do you want to live a longer life in good health? Simple practices can make some difference, such as exercise or calorie restriction. But over the long haul all that really matters is progress in medicine: building new classes of therapy to repair and reverse the known root causes of aging. The sooner these treatments arrive, the more lives will be saved. Find out how to help »June 4th, 2021
CD4 / CD8 T CELL RATIO AS A MEASURE OF IMMUNE AGING__ Permalink
__ No Comments Yet
__ Add a Comment
__ Posted by Reason
The state of the aged adaptive immune systemcan be assessed
in a practical way in animal studies, such as via exposure toinfluenza or other
well-calibrated infectious disease. This assessment is also carried out on the human population as a whole in every influenza season, but for individual humans one wants a metric that is a little less do or die. The adaptive immune system is made up of many different subtypes of B cell and T cell , each serving a different purpose. While the overall population of T cells remains fairly consistent with age, the size of different T cell subtype populations changes in characteristic ways. Based on this, metrics of immune function can be created. T cells are characterized by the surface markers they expose, and the number of cells with a given marker or combination of markers can be counted in a flow cytometry machine, given a blood sample to work with. There are a very large number of these markers, and countless combinations, but some are established to be much more important than others. CD4 is a marker of T helper cells , which serve a variety of coordinating roles in the immune response, for example, while CD8 is a marker of cytotoxic T cells, responsible for
killing errant cells and pathogens . This is an overly simplistic description of a very complex array of cell states and behaviors, but it is useful, as demonstrated by the fact that the CD4/CD8 ratioof T cells in
a blood sample does, on balance, reflect the state of the immune system as a whole. A low CD4/CD8 ratio correlates with a greater degree of frailtyand comorbidity
in older people.
Immunological features beyond CD4/CD8 ratio values in olderindividuals
> _
> The CD4/CD8 T-cell ratio is emerging as a relevant marker of > evolution for different pathologies and therapies, including > cardiovascular diseases> . Immune
> alterations related to cellular immunosenescence > , together with > persistent inflammation> ,
> are known to be involved in the process of deleterious aging, which > underlies the failure to maintain global health status during aging. > The CD4/CD8 ratio might be related to cellular immunosenescence, and > potential factors affecting the CD4/CD8 ratio in older people have > been extensively studied.>
> Cytomegalovirus
> infection has been widely reported as the main cause of CD8 T-cell > oligoclonal expansion> .
> Additionally, free radicals> , which
> accumulate during aging, may have an impact because subjects with an > inverted CD4/CD8 ratio exhibit reduced levels of antioxidant > defenses and higher > oxidative stress . > Hence, factors associated with cumulative cellular senescence> and oxidative
> stress appear to trigger a reduction in the CD4/CD8 ratio; however, > the immunological features beyond CD4/CD8 T-cell ratio values > require further exploration.>
> It is reasonable that CD4/CD8 T-cell ratio values, particularly in > older people, might reflect different degrees of immune capabilities > both for responding to antigens > and for preserving health > status in this population. Although thymic output is the main > regulator of T-cell homeostasis> ,
> whether it relates to the CD4/CD8 T-cell ratio in older individuals > has not yet been explored. Notably, the thymus > undergoes progressive atrophy > throughout life, > reducing its activity by approximately 3% per year until middle age, > when it slows down to less than 1% per year.>
> Nevertheless, the thymus remains active in adults, contributing to > the renewal of the pool of naïve T-cells > , even though thymic > function is highly variable in older people. In fact, intrathymic > CD4+CD8+ double-positive T cells > obtained from thymic > biopsies correlate not only with age (negative) but also with the > frequency of naïve T cells (positive). Interestingly, a > relationship between thymic function and the CD4/CD8 T-cell ratio > exists in HIV infection, which > is a different scenario but shares several immunosenescence traits > with aging. On the other hand, it is also reasonable that CD4/CD8 > T-cell ratio values might correlate with different inflammatory > profiles. To better understand the biological meaning of the CD4/CD8 > ratio in the elderly, we explored the phenotypic profiles of both > CD4 and CD8 T-cells, as well as the thymic output and several > inflammation-related parameters, in a population of older subjects > classified according to CD4/CD8 ratio value.>
> The lower CD4/CD8 ratio group showed a lower thymic output and > frequency of naïve T-cells, concomitant with increased mature > T-cells. In these subjects, the CD4 T-cell subset was enriched in > CD95 + but depleted of > CD98 + cells. The regulatory> T-cell (Treg)
> compartment was enriched in CTLA-4 > + cells. The CD8 T-cell pool > exhibited increased frequencies of CD95+ cells but decreased > frequencies of integrin-β7> + cells.
> Interestingly, in the intermediate CD4/CD8 ratio group, the CD4 pool > showed greater differences than the CD8 pool, mostly for cellular> senescence.
>
> Regarding inflammation, only high sensitivity CRP > was elevated in > the lower CD4/CD8 ratio group; however, negative correlations > between the CD4/CD8 ratio and β2-microglobulin> and soluble
> CD163 were detected. These > subjects displayed trends of more comorbidities and less > independence in daily activities. Altogether, our data reveal that > different thymic output and immune profiles for T-cells across > CD4/CD8 ratio values that can define immune capabilities, affecting > health status in older individuals. Thus, the CD4/CD8 ratio may be > used as an integrative marker of biological age.> _
June 4th, 2021
CONSIDERING EXERCISE AS A MEANS TO SLOW THE PROGRESSION OF AGING__ Permalink
__ Read 4 Comments
__ Add a Comment
__ Posted by Reason
It is well known that regular exercise can slow the progression of many age-related declines, and reduce mortality risk in late life. Different forms of exercise, such aerobic exerciseversus strength
training , appear to produce different, overlapping benefits. This is concretely demonstrated in animal models, while the human epidemiological data, which can only show correlations, is supportive of the thesis that exercise produces changes in metabolism that modestly slow the onset of age-relateddeclines.
> _
> Exercise is a lifestyle intervention with known antiaging effects > capable of counteracting several of the hallmarks of aging > including senescence > and age-associated> inflammation
> .
> We propose that 5' adenosine monophosphate-activated protein kinase> (AMPK)
> can orchestrate many of the antiaging effects of exercise through > its regulation of diverse cellular pathways in the setting of > energetic stress.>
> Activating AMPK is sufficient to extend lifespan in many organisms. > It is naturally activated in response to muscle contraction and > nutrient depletion> ,
> both of which are components of exercise. Whereas most of the > studies supporting AMPK as an antiaging strategy are based in animal > models, the use of metformin > (an AMPK activator) in > clinical trials (TAME)>
> as an antiaging drug is based on its capacity to delay heart disease> , cancer,
> cognitive decline, and death in people with diabetes > . These results > suggest that the antiaging effects of AMPK are also relevant in > humans, but the molecular mechanisms underlying these effects remain > to be determined.>
> A landmark 21-year longitudinal> study that
> followed runners and compared them with a sedentary group, found > that those who exercise had a significantly lower risk of dying > (15%) during that time frame than the sedentary group (34%) while > also having reduced disabilities. It is unclear whether the > beneficial effects of exercise in this study were due to a delay in> secondary aging
>
> or to countering of the effects of sedentarism > . Regardless of this > limitation, numerous studies have shown that maintaining a minimum > quantity and quality of exercise improves cardiorespiratory fitness> and muscle
> function, flexibility, and balance.>
> Current guidelines recommend a minimum of 150 min/week of moderate > intensity aerobic activity for maximum longevity benefits, with > higher duration and intensity increasing cardiovascular and > metabolic effects. It has been estimated that performing three to > five times the recommended physical activity (450-750 min/week) > reaches the maximal healthspan benefit that can be achieved with > endurance exercise. Strength training > should be added to > minimize loss of muscle mass that is characteristic of aging and> disease.
>
> In summary, exercise is an effective strategy to prevent aging and > enhance longevity and health span both on a clinical and a cellular > level due to its capacity to modulate all nine hallmarks of aging > . Additionally muscle, > one of the main systemic effectors of exercise, is recognized as an > endocrine organ > that produces and releases myokines > , implying a complex cross > talk between muscles and other tissues. The AMPK pathway, a > well-known mediator of exercise effects in muscle could be activated > in different tissues and drive many of the health-promoting and > lifespan-extending capabilities of exercise. We propose that it is a > central effector node able to impact the hallmarks of aging and > integrate the effects of exercise on many tissues.> _
Link: https://doi.org/10.18632/aging.203051June 4th, 2021
SIRT6 OVEREXPRESSION EXTENDS LIFE IN MICE__ Permalink
__ Read 7 Comments
__ Add a Comment
__ Posted by Reason
There was a great deal of interest in sirtuin 1 in relation to aging and life span some years ago, very much overhyped as it turned out. Nothing of any practical use emerged from that research. Sirtuin 6 has a more robust effect on mouse life span, perhaps via improvement of mitochondrial function . Like all such exercises in metabolic manipulation that attempt to slow the progression of aging, targeting processes known to be involved in cellular responses to stress, it is likely that the beneficial effects diminish as species life span increases. A sirtuin with better results in mice remains unlikely to move the needle all that much on human life span.> _
> Of the seven mammalian sirtuins > , SIRT1-7, SIRT1, and SIRT6 > protein levels increase upon dietary restriction>
> and fasting in various mouse tissues and human cell lines. > Interestingly, whole-body SIRT1 overexpression > in mice leads to > improvement in parameters reflecting healthspan, but not lifespan. > Whereas whole-brain-specific SIRT1 overexpression did not affect > lifespan and brain plasticity> , hypothalamic
> SIRT1 overexpression > delays aging. However, whole-body SIRT6 overexpression in mice > background leads to a significant extension of male lifespan and > healthspan, associated with inhibition of IGF-1>
> signaling.
>
> Here, we show that overexpression of SIRT6, but not SIRT1, extends > lifespan in C57BL/6JOlaHsd mice > in both sexes. > SIRT1 does not synergize with SIRT6 to further increase median or > maximal survival. Overexpression of SIRT6 reduced the age-related > metabolic decline in energy metabolism > pathways and inhibited > frailty by preserving hepatic> NAD+
>
> levels, gluconeogenesis> capacity, and
> maintenance of normoglycemia > , key markers of > healthy aging. These results emphasize the potential of targeting > SIRT6 for maintaining energy metabolism and reducing age-related> frailty.
> _
Link: https://doi.org/10.1038/s41467-021-23545-7June 3rd, 2021
EXPRESSION OF REPROGRAMMING FACTORS IN MYOCYTES IMPROVES MUSCLEREGENERATION
__ Permalink
__ Read 1 Comment
__ Add a Comment
__ Posted by Reason
The research community is devoting an increasing amount of attention to the use of cellular reprogrammingin vivo
as a basis for therapies, rather than as a way to produce pluripotent cells outside the body. It has been only fifteen years or so since the first practical reprogramming approach was developed, using Yamanaka factors to transform somatic cells into induced pluripotentstem cells
. Only in
the past few years have researchers tried in earnest to introduce reprogramming factors into living animals in order to produce benefits to health and tissue function. It is somewhat surprising, perhaps, that this can be done without the immediate consequences of cancer and loss of tissue function, but the dose makes the poison. Reprogramming of cells not only changes their state, but also resetsepigenetic marks
characteristic of cells in aged tissues and restores lost mitochondrial function.
Research suggests that this beneficial restoration of function can be to some degree decoupled from the change in cell state, and that the process of undergoing programming is a complicated time course, with important differences by cell type, that can be manipulated in numerous ways. Cells can be partially reprogrammed for a short time,
gaining restored function, without losing their state and behavior. This is a necessary goal if reprogramming is to be deployed as a therapy to restore function in aging tissues. In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche> _
> Reprogramming of somatic cells to a pluripotent state by > overexpressing the > Yamanaka factors (Oct-3/4 ,> Sox2 , Klf4
> , and c-Myc
> ) is a long and complex > process. Cellular reprogramming is widely utilized for disease > modeling in vitro . However, > reprogramming in vivo induces tumor development. Our lab showed that > partial reprogramming by short-term expression of reprogramming > factors ameliorated aging hallmarks> without tumor
> formation, opening a possible application of this approach in vivo. > Recently, other reports have demonstrated rejuvenation of dentate > gyrus cells, retinal> ganglion cells
> , chondrocytes
> , and muscle stem cells > using reprogramming factors, reinforcing its potential application > in clinical settings. Besides amelioration of cellular aging > hallmarks, reprogramming factors promote tissue regeneration in aged > mice. However, it is unknown whether OSKM-improved regeneration is > solely a result of its rejuvenating effect.>
> Muscle regeneration is primarily mediated by muscle stem cells > , also known as > satellite cells (SCs), which reside in a characteristic niche > located between the > basal lamina and plasma > membrane of myofibers > . The regenerative capacity > of SCs is influenced by both intrinsic modulators and the extrinsic > microenvironment . > We have shown that partial reprogramming promotes skeletal muscle > regeneration in 12-month-old mice, but these studies were performed > by expressing OSKM systemically (i.e., in all cell types). It is > therefore unclear whether intrinsic or niche-specific factors > contributed to the observed improvement in muscle regeneration.>
> In this work, we generate myofiber- and SC-specific OSKM induction > mouse models to investigate the effect of OSKM induction on > extrinsic and intrinsic modulators of SCs, respectively. In > addition, we chose young mice to investigate whether the improvement > of regeneration can be achieved by OSKM induction regardless of its > rejuvenating effect. Our data shows that myofiber-specific OSKM > induction accelerates muscle regeneration through downregulating the > myofiber-secreted niche factor, Wnt4 > , to induce the activation and > proliferation of SCs. In contrast, SC-specific OSKM induction does > not improve muscle regeneration in young mice. We conclude that > partial reprogramming via OSKM can remodel the SC niche to induce SC > activation and proliferation and accelerate muscle regeneration.> _
June 3rd, 2021
THE HIGHLY ACTIVE TSIMANE PEOPLE EXHIBIT SLOWER NEURODEGENERATION WITHAGE
__ Permalink
__ Read 1 Comment
__ Add a Comment
__ Posted by Reason
You may recall the data on cardiovascularhealth published
in recent years for the Tsimane population in Bolivia , characterized by a physically active lifestyle and a diet that lacks most of the problem components found in wealthier parts of the world. The rates of cardiovascular diseaseare far lower
in the Tsimane
than in US populations. While there are certainly inevitable processesof aging that can
only be addressed by the development of new medical biotechnologies,
it is also the case that a sizable fraction of cardiovascular and muscle degeneration in the wealthier populations of the world appears to be self-inflicted. Too little physical activity and a diet containing too many calories comes with costs. As the research materials here illustrate, that cost also falls on the brain.> _
> Although people in industrialized nations have access to modern > medical care, they are more sedentary and eat a diet high in > saturated fats. In contrast, the Tsimane have little or no access to > health care but are extremely physically active and consume a > high-fiber diet that includes vegetables, fish and lean meat. "The > Tsimane have provided us with an amazing natural experiment on the > potentially detrimental effects of modern lifestyles on our health.">
> The researchers enrolled 746 Tsimane adults, ages 40 to 94, in their > study. To acquire brain scans, they provided transportation for the > participants from their remote villages to Trinidad, Bolivia, the > closest town with CT scanning equipment. That journey could last as > long as two full days with travel by river and road. The team used > the scans to calculate brain volumes and then examined their > association with age for Tsimane. Next, they compared these results > to those in three industrialized populations in the U.S. and Europe.>
> The scientists found that the difference in brain volumes between > middle age and old age is 70% smaller in Tsimane than in Western > populations. This suggests that the Tsimane's brains likely > experience far less brain atrophy than Westerners as they age; > atrophy is correlated with risk of cognitive impairment, functional > decline, and dementia . The > researchers note that the Tsimane have high levels of inflammation > , which is typically > associated with brain atrophy in Westerners. But their study > suggests that high inflammation does not have a pronounced effect > upon Tsimane brains.>
> According to the study authors, the Tsimane's low cardiovascular > risks may outweigh their infection-driven inflammatory risk, raising > new questions about the causes of dementia. One possible reason is > that, in Westerners, inflammation is associated with obesity and > metabolic causes. In the Tsimane, however, it is driven by > respiratory, gastrointestinal, and parasitic infections. Infectious > diseases are the most prominent cause of death among the Tsimane.> _
Link:
https://news.usc.edu/187075/tsimane-amazon-indigenous-people-healthy-brain-aging-usc-study/June 3rd, 2021
OISIN BIOTECHNOLOGIES SEEKS TO TREAT CHRONIC KIDNEY DISEASE WITH SENOLYTIC SUICIDE GENE THERAPY__ Permalink
__ Read 6 Comments
__ Add a Comment
__ Posted by Reason
Oisin Biotechnologies is one of the older startup biotech companies in the still young and growing longevity industry. The company develops a programmable suicide gene therapyplatform
,
initially targeted at the selective destruction of senescent cellsand cancerous
cells. Of interest in a recent press release regarding funding is the note that their senolytic program will be used to treat chronic kidney disease. Other groups
are running human trials of the dasatinib and quercetin combination as a treatment for chronic kidney disease. Positive data there will help Oisin Biotechnologies, in the sense that it will further validate the use of senolytics as a class of therapy for this condition, but at the same time set a bar for success that will need to be beaten.> _
> Oisín Biotechnologies, a privately held, preclinical biotechnology > company focused on mitigating the effects of age-related diseases, > today announced it has completed an oversubscribed round raising $5 > million in new seed funding. Led by early-stage investing firm > Althea Group, LLC , the round brings > Oisín's total funding to $9.5 million. Oisín will use the proceeds > to advance its preclinical pipeline, including its most advanced > investigational therapy aimed at chronic kidney disease (CKD).>
> "The support for Oisín's novel approach to slowing or halting > age-related diseases has been strong. Chronic kidney disease (CKD), > our initial therapeutic focus, has seen little in the way of > therapeutic advances over the past several decades. We believe > Oisín is well positioned to address this unmet medical need and > will continue to explore other applications in tandem.">
> Oisín's highly precise, DNA-based interventions are designed to > clear senescent cells, which can trigger aging pathologies and > shorten lifespan, from the body. Its proprietary technology is a > third-wave innovation that uses a novel proteo-lipid vehicle drug > delivery platform to induce > a senescent cell to trigger apoptosis > without harming > surrounding healthy cells. In preclinical studies, Oisín's > investigational therapeutics have significantly reduced senescent > cell burden in naturally aged mice and extended lifespan by more > than 20%, even when the treatment was started in old age.>
> Oisín expects the first readouts from its preclinical study in CKD > later this year. The initial data will inform its next series of > studies and eventually, its first proposed clinical trial design. > While using this latest funding to accelerate its CKD work, the > company is continuing to progress other planned studies in its > preclinical program, advance additional pipeline indications and > move towards a regulatory filing to begin its first clinical trial.> _
Link:
https://www.businesswire.com/news/home/20210527005467/en/Ois%C3%ADn-Biotechnologies-Raises-Seed-Funding-to-Advance-Therapies-for-Age-Related-DiseasesJune 2nd, 2021
THE LINKS BETWEEN AGING AND IMMUNE FUNCTION GO FAR BEYOND DEFENSEAGAINST PATHOGENS
__ Permalink
__ No Comments Yet
__ Add a Comment
__ Posted by Reason
The immune system is deeply integrated into tissue function throughout the body. This goes far beyond merely identifying and chasing down invaders such as fungi, bacteria, and viruses. Immune cells of various types also help to coordinate tissue maintenance, regeneration from injury, and the destruction of damaged, cancerous, and senescent cells. In the brain,
immune cells are involved in the maintenance and alteration of synaptic connections between neurons . Immune cells mediate inflammatory signaling, and that signaling is in turn highly influential on the behavior of other cells, altering tissue function, particularly when inflammation becomes chronic.
One possibly overly simplistic view of the evolution of the immune system is that its present state is a balance between (a) providing a good-enough defense against pathogens and errant cells, and (b) minimizing harmful side-effects resulting from the inflammatory response. Too aggressive a response and individuals will lapse into chronic inflammation and early death. Too little of a response, and the pathogens win, again causing early death. Somewhere there is a happy medium that allows enough individuals to reproduce to ensure evolutionary success. But there are likely many other trade-offs under constant selection pressure, as discussed in
today's open access paper. Functional conservation in genes and pathways linking ageing andimmunity
> _
> At first glance, longevity and immunity appear to be different > traits that have not much in common except the fact that the immune > system promotes > survival upon pathogenic infection. Substantial evidence however > points to a molecularly intertwined relationship between the immune > system and ageing. Although this link is well-known throughout the > animal kingdom, its genetic basis is complex and still poorly> understood.
>
> In this review, we combined curation and analysis of orthologs > between D. melanogaster> , C. elegans
> , mice, and
> humans to reveal that genes currently known to be pleiotropically > involved in immunity, > lifespan, and ageing reside in a few core pathways mediating the > immuno-ageing interplay. We identified 7 evolutionarily conserved> signalling
> cascades, the insulin /TOR>
> network, three MAPK>
> (ERK , p38
> ,
> JNK ), JAK
> /STAT
> , TGF-β
> , and
> Nf-κB pathways that act > pleiotropically on ageing and immunity. However, we highlight that > these pathways not only cross-talk, but also clearly act > pleiotropically to regulate pathogen resistance, lifespan, and > ageing among many other physiological processes such as metabolism > and stress resistance.>
> Our review demonstrates that loss of immune homeostasis > is a central determinant > of ageing across diverse phyla> . Yet, whether
> immunosenescence
> and the age-associated decline in other traits is a cause or result > of ageing remains a fundamental problem difficult to resolve. > Knowing the exact time and place of changes related to immunity and > ageing would be a huge step in answering this question. Moreover, > how environmental effects, including life-long pathogenic > challenges, variation in the microbiome > , or nutrition affect > age-related changes in immunity is poorly understood. To date most > studies are restricted in resolution, particularly in terms of > analysed tissues, time points, phenotypes, and experimental > conditions. Cutting-edge technologies such as single-cell sequencing > can be useful > in that respect and could be utilized to characterize molecular > changes during ageing and infection in specific cell types. In > combination with genome-wide> CRISPR
> knockout
> screens, new
> immuno-ageing genes can be discovered and the cross-talk between > immunity and ageing further deciphered.>
> Currently, the level of detail needed to solve the causality enigma > of ageing is likely not achievable in humans but may be addressed in > shorter lived model organisms that are easier to manipulate. Once we > understood ageing at this unprecedented level, it will be possible > to optimize lifestyle factors and emerging drug therapies treating > senescence to facilitate healthy ageing and extend lifespan.> _
June 2nd, 2021
SENOLYTIC TREATMENT REVERSES AGE-RELATED LOSS OF KIDNEY REGENERATIONIN MICE
__ Permalink
__ Read 1 Comment
__ Add a Comment
__ Posted by Reason
Senescent cells
accumulate with age and cause a great deal of harm in the aged body. Their numbers are not thought to be very high in most tissues, perhaps a few percent of all cells by late life, but senescent cells secrete a potent mix of signalsthat has a
widespread disruptive effect. This signaling spurs chronicinflammation
and causes malfunctioning of the normal processes of tissue regeneration and maintenance, amongst other issues. In organs like the kidney, this results in a lack of resilience to injury, increased fibrosis , and eventually chronic kidney disease. Researchers
have shown that senolytic treatment to destroy senescent cells is beneficial in animal models of chronic kidney disease,
and a human trial is ongoing,
with encouraging early results. Here, researchers show that senolytic treatment can also restore some degree of lost regenerative capacityin aged kidneys.
> _
> The ability of the kidney to regenerate successfully after injury is > lost with advancing age, chronic kidney disease, and after > irradiation . The > factors responsible for this reduced regenerative capacity remain > incompletely understood, with increasing interest in a potential > role for cellular senescence in determining outcomes after injury. > Here, we demonstrated correlations between senescent cell load and > functional loss in human aging and chronic kidney diseases including > radiation nephropathy.>
> We dissected the causative role of senescence in the augmented > fibrosis occurring after injury in aged and irradiated murine > kidneys. In vitro > studies on human proximal > tubular epithelial cells> and in
> vivo mouse studies > demonstrated that senescent renal epithelial cells > produced multiple > components of the senescence-associated secretory phenotype>
> including transforming growth factor β1 > , induced fibrosis, and > inhibited tubular>
> proliferative capacity after injury.>
> Treatment of aged and irradiated mice with the senolytic drug > ABT-263 reduced senescent > cell numbers and restored a regenerative phenotype in the kidneys > with increased tubular proliferation, improved function, and reduced > fibrosis after subsequent ischemia-reperfusion injury > . Senescent cells > are key determinants of renal regenerative capacity in mice and > represent emerging treatment targets to protect aging and vulnerable > kidneys in man.> _
Link: https://doi.org/10.1126/scitranslmed.abb0203June 2nd, 2021
HUMAN BIOMARKER OF AGING MODELING FROM GERO__ Permalink
__ No Comments Yet
__ Add a Comment
__ Posted by Reason
The Gero staff have in recent years performed scientifically interesting modeling of data, from aging animals and humans, in support of their drug development program. One might look back on their categorization of age-related degeneration into two components, which they call "aging" and "frailty", but which are really just labels for what appear to be two distinct aspects of biomarker progression with chronological age that emerge from their data. Humans and mice have quite different balances of "aging" versus "frailty", which could in principle inform unbiased screening programs for drugs that might slow the progression of aging. In this open access paper, the Gero team look at human biomarkers of aging over time to build a model of loss of resilience; again scientificallyinteresting.
> _
> Most important factors that are strongly associated with age are > also known as the hallmarks of aging > and may be, at least in > principle, modified pharmacologically. In addition to that, the > dynamic properties such as physiological resilience measured as the > recovery rate from the organism state perturbations were also > associated with mortality and thus may serve as an early warning > sign of impending health outcomes.>
> We conducted a systematic investigation of aging, organism state > fluctuations, and gradual loss of resilience in a dataset involving > multiple Complete Blood Counts (CBC)> measured over
> short periods of time (a few months) from the same person along the > individual aging trajectory. Instead of focusing on individual > factors, to simplify the matters, we followed and described the > organism state by means of a single variable, henceforth referred to > as the dynamic organism state indicator (DOSI) in the form of the > all-cause mortality model predictor. First, we observed that early > in life the DOSI dynamics quantitatively follows the universal > ontogenetic growth > trajectory. Once the growth phase is completed, the indicator > demonstrated all the expected biological age properties, such as > association with age, multiple morbidity > , unhealthy lifestyles, > mortality and future incidence of chronic diseases.>
> Late in life, the dynamics of the organism state captured by DOSI > along the individual aging trajectories is consistent with that of a > stochastic process > (random walk) on > top of the slow aging drift. The increase in the DOSI variability is > approximately linear with age and can be explained by the rise of > the organism state recovery time. The latter is thus an independent > biomarker of aging and a characteristic of resilience. Our analysis > shows that the auto-correlation time of DOSI fluctuations grows (and > hence the recovery rate decreases) with age from about 2 weeks to > over 8 weeks for cohorts aging from 40 to 90 years. The divergence > of the recovery time at advanced ages appeared to be an > organism-level phenomenon.>
> We put forward arguments suggesting that such behavior is typical > for complex systems near a bifurcation (disintegration) point and > thus the progressive loss of resilience with age may be a dynamic > origin of the Gompertz law>
> of mortality. Finally, we noted, by extrapolation, that the recovery > time would diverge and hence the resilience would be ultimately lost > at the critical point at the age in the range of 120-150 years, thus > indicating the absolute limit of human lifespan, absent novel> interventions.
> _
Link: https://doi.org/10.1038/s41467-021-23014-1June 1st, 2021
THINKING OF PROGERIA AS ACCELERATED AGING ONLY PRODUCES CONFUSION__ Permalink
__ Read 1 Comment
__ Add a Comment
__ Posted by Reason
Progeria (more correctly Hutchinson-Gilford progeria syndrome ) is a condition in which a protein vital to cell structure, lamin A , is mutated. Cells with abnormal structure due to loss of function in lamin A are dysfunctional in many ways, including being very prone to senescence. Patients rarely
live past their teens, and exhibit a range of conditions such as cardiovascular diseasethat appear
similar to the age-related diseases suffered in later life by non-mutated people. Calling progeria accelerated aging is incorrect and a source of confusion, however, as illustrated by a recent commentary on the topic.
What Do Treatments For Accelerated Aging Tell Us About Normal Aging?> _
> Children with progeria have a mutation in the relevant gene; instead > of producing lamin A, they produce a defective mutant protein called > progerin . The cell tries to > build the nuclear lamina > out of defective > progerin instead of normal lamin A, and as a result the cell nucleus > is screwed up and can't maintain a normal shape. So then aging > happens? My sources don't seem to have a great explanation of this. > The UniProt database>
> says that this "acts to deregulate mitosis > and DNA damage > signaling, leading to > premature cell death and senescence". This paper> goes a
> little further, saying that the screwiness in the nuclear lamina > prevents DNA repair > proteins from doing their job.>
> So a unified theory of progeria goes: the lamin mutation causes > accumulation of defective protein in the nucleus > , preventing DNA repair. > This makes people accumulate DNA damage faster, and since DNA damage > is a major cause of aging> ,
> it makes these people age more quickly. Lornafarnib > interferes with the > production of the defective progerin protein. All of this suggests > lornafarnib shouldn't help prevent normal aging. After all, normal > aging is caused by lots of processes including gradual expected > accumulation of DNA damage - not just the downstream effects of one > weird mutant protein.>
> ...except that in doing this research I kept finding people saying > that maybe some of aging is caused by this one weird mutant protein. > I don't really get what's going on here. I know that often, as > age-related damage degrades DNA, a lot of weird malformed proteins > pop up and accumulate. Maybe progerin is one of these proteins and > causes some of the problems commonly associated with aging?> _
Age-related diseases occur due to damage and loss of function. As a result of damage, cells are misbehaving, broken, lost and not replaced, following incorrect programs, and so forth. In normal aging, this is the result of a particular balance of various forms of damageand their
consequences: cellular senescence, buildup of
resilient metabolic waste,
mitochondrial damage and dysfunction, stem cell decline, and so forth. In progeria, a completely different form of damage dominates, with the result that cells are misbehaving, broken, lost and not replaced, and so forth. It is not that different, conceptually, from a slow poisoning that interferes with vital cellular functions, some forms of which can also superficially replicate the effects of aging. The point here being that any form of damage that leads to widespread cellular dysfunction, that is not so severe as to kill the patient quickly, will likely have among its outcomes something that looks like a range of age-related conditions. That doesn't make it aging, nor does it say anything at all about how to go about addressing aging itself. The best way to approach aging is to periodically repair the cell and tissue damage that causes it. The strategies for that repair depend absolutely on the type of damage being repaired. Treatments for poisoning or progeria will, on balance, have little to no relevance to the strategies needed to effectively treat aging. In the case of progeria this is slightly complicated by the discovery that there is a little broken lamin A to be found in normal old humans.
Present thinking is that this is likely connected to cellularsenescence . The
numbers of senescent cells rise with age,
and are clearly important to aging, but likely not because of lamin A. Alternatively, the creation of broken lamin A is happening at a very low level throughout the body as a result of other forms of damage and dysfunction in cells, and it is thus a downstream effect and not all that relevant. The challenge in much of biochemistry is that absent a way to selectively eliminate one mechanism without affecting all of the others, it is very hard to say which of these mechanisms are actually more or less important to the observed outcome. Another challenge is that researchers do tend to exaggerate the relevance of the work they are doing in order to assist in the grant writing process, but that is a whole different topic. So of course anyone writing a paper on lamin A in normal aging is going to say, absent proof otherwise, that it looks like this may be relevant to aging, and more research into this mechanism is justified. Is malformed lamin A at all relevant to normal aging? Setting aside the reasonable guess of "no", one can imagine a study of senolytic drugs to clear senescent cells in normally aged animals or humans, with before and after tests of the level of malformed lamin A in various tissues in the body. That would be informative. An effective gene therapy to deliver functional lamin A would also be informative, but the present state of gene therapy vectors is that it is very challenging to deliver a vector even close to globally in the body at usefully high levels. Near all of it ends up in the liver and lungs, usually. That would likely be beneficial for progeria patients, while not beneficial enough to save their lives, but seems unlikely to tell us much in a normally agedanimal or human.
June 1st, 2021
INTERMITTENT FASTING ENHANCES LONG TERM MEMORY IN MICE TO A GREATER DEGREE THAN MILD CALORIE RESTRICTION__ Permalink
__ Read 2 Comments
__ Add a Comment
__ Posted by Reason
It is always interesting to see studies that compare the outcomes ofcalorie restriction
and intermittent fasting. In this case, researchers provide evidence to suggest that, at the same mild overall calorie reduction versus adlibitum feeding,
intermittent fasting produces larger effects on memory function. If those effects are driven in large part by the biochemistry of hunger, then we might think that intermittent fasting produces more time spent hungry, and thus a larger effect size. The choice of amount of calorie reduction may well influence the outcome of any such comparison for other reasons, however.> _
> Daily calorie restriction (CR) and intermittent fasting (IF) enhance > longevity and cognition. Despite the positive effects of CR and IF > in neurodegenerative> and affective
> conditions, the > specific behavioral contributions and mechanisms that differentiate > both interventions remain largely unknown. Answering these questions > is pivotal to adapting these regimens to human populations, given > the challenges of adhering to a long-term CR regimen when compared > to the improved adherence to variations of the IF paradigm.>
> Here, we directly compared the effects of IF to a matched 10% daily > CR regimen upon learning and memory in mice. A 10% energy> restriction
> protocol was chosen for the CR group following the observation that > IF mice overall consume 10% less calories on a weekly basis. IF > improved long-term retention memory to a greater extent than CR and > was associated with increased adult hippocampal> neurogenesis
> and upregulation of the > longevity gene Klotho > . Though klotho > protein is produced primarily in the kidney, it is also highly > expressed in some > brain areas, including the dentate gyrus > of the hippocampus and > in particular by its mature neurons> .
>
> The function of klotho in the brain is still largely unknown but it > has been proposed that it plays an important role in cognition > because increased serum > levels of klotho were > associated with increased cognitive ability in humans and rodents. > Here, we confirm previous evidence suggesting that Kl is an > important regulator of adult hippocampal neurogenesis and propose it > as a novel molecular player through which IF may enhance cognitive> performance.
> _
Link: https://doi.org/10.1038/s41380-021-01102-4June 1st, 2021
GENE THERAPY TO ADD A NEW PHOTOSENSITIVE PROTEIN TO THE RETINA__ Permalink
__ No Comments Yet
__ Add a Comment
__ Posted by Reason
Researchers have delivered a non-human photosensitive protein to the retina of a patient long blind from the loss of photoreceptor cellscaused by retinitis
pigmentosa . The
outcome as described is not as good as the results produced by implantation of grids of electrodes into the retina,
but that strategy has been under development for a somewhat longer number of years. This approach is in the very early stages: it is unclear as to how well one can engineer the retina to use alternative means of translating light into signals to the optic nerve , and how well the brain will adapt to such new sources of information over time. Still, the prospects for the blind are becoming more promising year after year, as the number of approaches to regeneration or replacement grows.> _
> Optogenetics may enable > mutation-independent, circuit-specific restoration of neuronal > function in neurological diseases. Retinitis pigmentosa is a > neurodegenerative > eye disease where loss of photoreceptors> can lead to
> complete blindness. In a blind patient, we combined intraocular> injection of
> an adeno-associated viral vector> encoding the
> channelrhodopsin ChrimsonR> with light
> stimulation via engineered goggles. The goggles detect local changes > in light intensity and project corresponding light pulses onto the > retina in real time to activate optogenetically transduced> retinal
> ganglion cells
> .
>
> The patient perceived, located, counted and touched different > objects using the vector-treated eye alone while wearing the > goggles. During visual perception, multichannel > electroencephalographic> recordings
> revealed object-related activity above the visual cortex > . The patient could not > visually detect any objects before injection with or without the > goggles or after injection without the goggles. This is the first > reported case of partial functional recovery in a neurodegenerative> disease after
> optogenetic therapy.> _
Link: https://doi.org/10.1038/s41591-021-01351-4May 31st, 2021
A GREAT DEAL OF WORK LIES AHEAD IN THE DEVELOPMENT OF IN VIVO REPROGRAMMING AS A THERAPY__ Permalink
__ Read 3 Comments
__ Add a Comment
__ Posted by Reason
Reprogramming of
ordinary somatic cells into induced pluripotent stem cells (iPSCs)was
initially thought to be a way to obtain all of the patient matched cells needed for tissue engineeringor cell therapies
. A great deal of work has gone towards realizing that goal over the past fifteen years or so; the research community isn't there yet, but meaningful progress has taken place. Of late, another line of work has emerged, in that it might be possible to use partial reprogramming as a basis for therapy,
delivering reprogramming factors into animals and humans in order to improve tissue function, without turning large numbers of somatic cells into iPSCs and thus risking cancer or loss of tissue structureand function.
Reprogramming triggers some of the same mechanisms of rejuvenation that operate in the developing embryo,
removing epigenetic marks characteristic of aged tissues, and restoring youthful mitochondrial function . It cannot do much for forms of damage such as mutations to nuclear DNA or buildup of resilient metabolic waste,
but the present feeling is there is nonetheless enough of a potential benefit to make it worth developing this approach to treatments for aging. Some groups have shown that partial reprogramming - via transient expression of reprogramming factors - can reverse functional losses in cells from aged tissues without making those cells lose their differentiatedtype. But
this is a complicated business. Tissues are made up of many cell types, all of which can need subtly different approaches to safereprogramming.
Today's open access preprint is illustrative of the amount of work that lies ahead when it comes to the exploration of in vivo reprogramming. Different cell types behave quite differently, will require different recipes and approaches to reprogramming, different times of exposure, and so forth. It makes it very hard to envisage a near term therapy that operates much like present day gene therapies , meaning one vector and one cargo, as most tissues are comprised of many different cell types all mixed in together. On the other hand, the evidence to date, including that in the paper here, suggests that there are ways to create the desired rejuvenation of epigenetic patterns and mitochondrial function without the risk of somatic cells dedifferentiating into stem cells.
Partial reprogramming restores youthful gene expression through transient suppression of cell identity> _
> Aging induces broad gene expression > changes across > diverse mammalian cell types, and these changes have been linked to > many of the prominent hallmarks of aging > . Cell reprogramming > experiments have shown that young animals can develop from adult > cells and aging features can be erased through complete > reprogramming to pluripotency > . Recent reports have > further suggested that transient expression of the Yamanaka factors > (SOKM) is sufficient to > reverse features of aging and improve cell function. However, it was > unclear whether these transient reprogramming interventions suppress > somatic cell identities, activate late-stage pluripotency programs, > or whether alternative reprogramming strategies could restore > youthful gene expression.>
> Here, we investigated these questions using single cell measurements > of gene expression to capture the phenotypic > trajectory of transient > reprogramming and evaluate the impact of alternative reprogramming > methods. We found that transient reprogramming suppressed somatic > cell identities and upregulated hallmark pluripotency programs, > contrary to some previous reports but consistent with timecourse > iPSC reprogramming experiments and lineage-tracing studies of > transient SOKM expression. By inferring RNA > velocity and applying numerical > tools from dynamical systems, we also found that transiently > reprogrammed cells transition back toward their original gene > expression states after transit through an intermediate state. Our > single cell profiles therefore revealed transient cell states that > were likely masked in previous bulk measurements and support a model > in which transient reprogramming suppresses somatic identities that > are later reacquired through differentiation. Further experiments > profiling single cell populations at multiple time-points during > transient reprogramming will be necessary to confirm this> hypothesis.
>
> It remains unknown which of the Yamanaka Factors are required to > restore youthful gene expression, or which subsets might exhibit > distinct effects during transient reprogramming. Previous studies > have explored only one set of factors at a time, preventing accurate > comparisons to address these questions. Our pooled screens of all > possible Yamanaka Factor subsets revealed that combinations of 3-4 > Yamanaka Factors have remarkably similar effects, suggesting no > single factor is required to restore youthful gene expression. > Combinations of two Yamanaka Factors were also more similar to the > full SOKM set than to control > or single factor > perturbations, and all reprogramming factor combinations reduced an > aging gene expression score. Our screen demonstrates that no single > pluripotency factor is required to mask features of aging and > suggest oncogene -free > reprogramming strategies may also restore youthful gene expression.> Our multipotent
> reprogramming experiments in myogenic > cells further support > this suggestion, indicating that youthful gene expression may be > restored even without activating the pluripotency factors.>
> Restoring youthful gene expression can improve tissue function, > implying that transient reprogramming may be therapeutic. However, > pluripotent reprogramming is well-known to be an oncogenic process, > even when Myc is excluded from > the reprogramming set. While it has been reported that transient > reprogramming does not suppress somatic cell identities based on > bulk measurements, our single cell results show that somatic cell > identity is suppressed and late-stage pluripotency GRNs are > activated in a transitional cell state in multiple cell types. This > raises the possibility that even transient reprogramming may be > oncogenic. Identifying alternative reprogramming strategies to > restore youthful gene expression with lower neoplastic risk is > therefore desirable. Toward this aim, we have shown that transient > reprogramming with multiple subsets of the Yamanaka Factors induces > highly similar transcriptional effects to the full set, and that a > distinct multipotent reprogramming system can confer youthful > expression. These results suggest the feasibility of disentangling > the rejuvenative and pluripotency inducing effects of transient > reprogramming and serve as a resource for further interrogation of > transient reprogramming effects in aged cells.> _
May 31st, 2021
MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN ALZHEIMER'S DISEASE__ Permalink
__ No Comments Yet
__ Add a Comment
__ Posted by Reason
Mitochondria are the power plants of the cell, responsible for constructing chemical energy store molecules, adenosine triphosphate (ATP). With age,
mitochondria become increasingly dysfunction, performing less useful work while generating more reactive oxygen species (ROS)capable of
damaging cellular machinery via inappropriate oxidative reactions . Raised levels of ROS, or oxidative
stress, are just as much a feature of aging as mitochondrialdysfunction
.
Many researchers see oxidative damage to cells as important in age-related disease, but it is far from settled as to whether or not this mechanism is in fact important in comparison to others, such as, for example, reduced levels of the ATP needed to power cellularprocesses.
> _
> The exact mechanisms underlying Alzheimer's disease (AD) > remain unclear > despite comprehensive attempts to understand its pathophysiology > . The most prominent > theory postulates that, in AD, tau > and amyloid-β > negatively affect > neuronal cells by compromising energy supply and the antioxidant > response, causing > mitochondrial and synaptic > dysfunction. Neuronal activity is highly energy-dependent, and > neurons are particularly > sensitive to disruption in mitochondrial function. In addition, > mitochondria produce cellular energy (adenosine triphosphate; ATP) > and are also involved in many processes that are important for the > life and death of the cell, including the control of second > messenger levels, such as calcium ions (Ca2+)> and reactive
> oxygen species (ROS).>
> Importantly, mitochondrial dysfunction contributes to reduced ATP > production, Ca2+ dyshomeostasis > , and ROS generation. > Alterations in mitochondrial dynamics> and mitophagy
> occur in early-stage AD, > but the underlying mechanisms are poorly understood. Thus, studies > elucidating the mechanisms of mitochondrial abnormalities in AD will > facilitate a greater understanding of the pathogenesis> of this
> neurodegenerative disease > and potentially > contribute to the advancement of therapeutic strategies to protect > synaptic activity and subsequent cognitive function. Here, we review > studies that suggest a role of mitochondrial dysfunction and the > consequent ROS production in AD pathology and provide a context to > explain current and future therapeutic approaches. We suggest that > improving mitochondrial function should be considered an important > therapeutic intervention against AD.> _
Link: https://doi.org/10.3389/fnagi.2021.617588May 31st, 2021
SENESCENT CELLS AS A MECHANISM FOR WORSE OUTCOMES IN TRANSPLANTATIONOF OLDER ORGANS
__ Permalink
__ No Comments Yet
__ Add a Comment
__ Posted by Reason
Senescent cells
accumulate with age in tissues throughout the body. They secrete a mix of signals that provokes chronic inflammation,
disruption of tissue maintenance, and changes in cell behavior that lead to pathology . Targeted clearance of senescent cells has been shown to produce rejuvenation inmice
,
a reversal of many different age-related conditions, particularly those strongly linked to the chronic inflammation of aging. In this context, researchers here discuss the presence of greater numbers of senescent cells in older tissues as an important mechanism determining outcomes for patients following organ transplantation.> _
> Organ transplantation is the treatment of choice for end-stage-organ > failure. The supply of organs, however, is limited, resulting in > prolonged waiting times with many patients dying or becoming too ill > to be transplanted. Aging demographics have incrementally affected > the deceased donor population with older donors showing the by far > largest proportional increase. Organs from older donors are, at the > same time, underutilized, frequently discarded or not even> considered.
>
> The most obvious strategy that may close the gap between demand and > supply may thus be an optimized utilization of older organs from > deceased donors. Increased donor age, at the same time poses a > significant risk for adverse outcomes including more frequent > rejections due to an augmented immunogenicity > in aging. Most > relevantly, older organs have shown compromised long-term graft > outcomes with inferior graft survival rates in addition to increased > rates of chronic allograft > dysfunction in > kidney, heart, and lung transplantation.>
> Senescent cells accumulate with aging and have been identified as > critical in driving the immunogenicity of older organs linked to the > accumulation of cell-free mitochondrial DNA>
> that accelerate alloimmune > responses. Recent > evidence also suggests that senescent cells can induce a senescent > phenotype in adjacent cells> ,
> a potential mechanism on how the engraftment of older organs may > facilitate the spread of senescence. Depletion of senescent cells, > at the same time, has been shown to ameliorate a wide range of > age-associated disabilities and diseases.>
> Characteristically, senescent cells secrete a myriad of > pro-inflammatory, soluble molecules as part of their distinct > secretory phenotype> that have
> been shown to drive senescence and age-related co-morbidities > . Preliminary data show > that the transplantation of old organs limits the physical reserve > of recipient animals. Here, we introduce potential mechanisms and > consequences of prompting bystander senescence>
> and discuss clinically relevant aspects of senescent cell spread > when transplanting older organs. Although speculative, age-disparate > transplantation may also provide unique opportunities as the > transplantation of young organs may contribute to rejuvenation.> _
Link: https://doi.org/10.3389/fimmu.2021.671479__
First Steps
* __Read an Introduction to Living Longer * __Read the Fight Aging! FAQ * __Sign up for the Fight Aging! Newsletter * __Fund Meaningful Aging ResearchServices
* __Longevity Industry Consulting * __How to Start a Longevity Biotech Company The Root Causes of Aging * __Aging is Caused by Damage * __Accumulating Cross-Links * __Buildup of Amyloid Between Cells * __The Failing Adaptive Immune System * __The Failing Innate Immune System * __Declining Lysosomal Function * __Mitochondrial DNA Damage * __Nuclear DNA Damage * __Buildup of Senescent CellsArchives and Feeds
* __Monthly News and Blog Archives * __Newsletter Archive* __RSS Posts Feed
* __RSS Comments Feed * __Using the Fight Aging! Content FeedsRequired Reading
* __Calorie Restriction and Longevity * __Cryonics, the Necessary Backup Plan * __How to Argue for Longevity Science * __The Odds of Human Longevity Mutations * __The Need For Activism and Advocacy * __Nuanced Opposition to the FDA * __Potential Gene Therapy Targets * __Predicting the First Rejuvenation Therapies * __Self-Experiment to Fight Aging! * __SENS: Bringing an End to Aging * __Stem Cells and Regenerative Medicine * __Those Determined to Merely Slow Aging * __The Three Types of Aging Research * __Transhumanism and Human Longevity * __What is Robust Mouse Rejuvenation? * __Why Prioritize SENS Research? * __The Million Year Life Span Non-Profit Initiatives * __Age Reversal Network * __Alliance for Aging Research * __American Aging Association* __Betterhumans
* __Biogerontology Research Foundation * __Brain Preservation Foundation * __ELPIs Foundation for Indefinite Lifespans * __Forever Healthy Foundation * __Fundación Vidaplus * __Global Healthspan Policy Institute* __Heales
* __Health Extension * __International Longevity Alliance * __Life Extension Advocacy Foundation* __Lifespan.io
* __LongeCity
* __Major Mouse Testing Program * __Maximum Life Foundation * __Methuselah Foundation* __New Organ Prize
* __Open Longevity
* __Palo Alto Longevity Prize * __Regenerative Sciences Institute * __Science Against Aging(Translate
)
* __SENS Research Foundation The Longevity Industry * __Aging Biotech Info: Companies * __Aging Biotech Info: Conferences Relevant Venture Funds* __Apollo Ventures
* __Emerging Longevity Ventures * __Kizoo Technology Ventures* __LongeVC
* __Longevity Fund
* __Longevity Vision Fund* __Methuselah Fund
Benefiting from Medical Research * __How to Read Scientific Research * __Researching Therapies and Clinical TrialsObjections Answered
* __Boredom
* __Inequality and Economics* __Overpopulation
* __Stagnation and Slow Progress * __Progress Requires Death * __Immortal Dictators * __Being Older for Longer * __What About Retirement?Blogs of Interest
* __@ging
* __Aging and the genes(Translate
)
* __Aging Sciences - Anti-Aging Firewalls* __Alcor News
* __ALZFORUM
* __Biostasis
* __Brain Preservation Prize Blog * __Buck Institute News * __Cellular Senescence Blog * __Cryonics Magazine * __Deep, Healthy Lifespan Extension * __Ethical Technology Blog * __Foresight Institute* __Geroscience
* __h+ Magazine
* __Hourglass
* __Immortality Roadmap * __In Search of Enlightenment* __Josh Mitteldorf
* __Lifeboat Foundation Blog * __Life Extension Advocacy Foundation Blog* __Long Long Life
* __Longevity.Technology * __LongevityMarketcap Newsletter * __Longevity Advice* __Longevity Facts
* __Longevity Letter * __The Meaning of Life* __Metamodern
* __Methuselah Foundation News* __Nanodot
* __Ouroboros
* __The Rational Argumentator* __Rejuvenaction
* __Singularity Hub
* __Singularity Weblog* __Sonia Arrison
* __Tomorrow EditionCreative Commons
* All original content at Fight Aging! is published under the Creative Commons Attribution 4.0 International License . In short, this means that you are encouraged to republish and rewrite Creative Commons licensed Fight Aging! content in any way you see fit. We only ask that that you are polite and (a) link to the original, (b) attribute the author, and (c) attribute Fight Aging!. Home | FAQ | Fund Research | Services | Investing |Therapies |
Newsletter | Archives | Press Room | Resources |About
Read our terms and conditions and privacypolicy .
Details
Copyright © 2024 ArchiveBay.com. All rights reserved. Terms of Use | Privacy Policy | DMCA | 2021 | Feedback | Advertising | RSS 2.0