• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo

Fight Aging! Newsletter, December 16th 2019


  • Please log in to reply
No replies to this topic

#1 reason

  • Guardian Reason
  • 1,101 posts
  • 130
  • Location:US

Posted 15 December 2019 - 02:08 PM


Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,please visit:https://www.fightaging.org/newsletter/

Longevity Industry Consulting Services

Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/

Contents

  • Cancer Survivors have Double the Risk of Suffering a Later Stroke
  • Calorie Restriction as a Way to Slow Harmful Age-Related Changes in the Gut Microbiome
  • Ways in Which the Failing Lymphatic System Contributes to Age-Related Disease
  • Corpora Amylacea in the Clearance of Metabolic Waste from the Brain via Cerebrospinal Fluid Drainage
  • A Large Study of Aspirin Use Finds Reduced Mortality, Contradicting the Recent ASPREE Study Results
  • Low Lymphocyte Levels Correlate with Greater Mortality in Late Life
  • Are Benefits from Cardiac Stem Cell Therapy Due to an Immune Response to Transplanted Cells?
  • Investigating Circular RNAs in Cellular Senescence
  • Proteasomal Failure as a Contributing Cause of Protein Aggregation in Neurodegenerative Disease
  • Reviewing the Present Development of Biomarkers of Aging
  • A Survey of Existing Literature on Senescent Cell Burden by Age and Tissue in Humans
  • Variation in Early Life Stress Contributes to Differences in Lifespan in Genetically Identical Worms
  • Assessing Late Life Cardiovascular Risk from Mid-Life Cholesterol Levels
  • Clearance of Senescent Cells is Fast in Youth, Slow in Aging, Tipping the Balance Towards Accumulation
  • A Review of Efforts to Target Senescent Cells in Order to Treat Age-Related Disease

Cancer Survivors have Double the Risk of Suffering a Later Stroke
https://www.fightagi...a-later-stroke/

Surviving cancer comes with a well known loss of remaining life expectancy, roughly the same as being obese or a lifelong smoker. It is plausible that this is a consequence of the generation of large numbers of lingering senescent cells, resulting from radiotherapy and chemotherapy, still the dominant forms of cancer treatment. An increased burden of cellular senescence is certainly preferable to death by cancer, but these cells secrete a potent mix of inflammatory signals that disrupt tissue maintenance and immune function, encourage fibrosis, and increase the risk of numerous age-related conditions. Given that the accumulation of senescent cells is a cause of aging, increasing their presence might rightfully be regarded as an acceleration of aging.

Researchers here note one of the specific consequences of surviving cancer, its present day therapies, and continuing forward with an increased burden of senescent cells, which is a greatly increased risk of stroke. This and numerous other consequences might be alleviated in large part via the use of senolytic drugs to clear out senescent cells. The development of senolytics is still in its comparative infancy, but some of the existing senolytics compounds are in human trials, are cheap and readily available, have been shown to clear senescent cells in human patients, and there is little other than regulatory barriers to prevent their wider adoption as a treatment for a range of age-related conditions. Consequently, testing their ability to reduce the impact of cancer therapy on patients only requires a trial sponsor, the funds, and the will to get started.

Notably, the authors of this open access paper do not mention cellular senescence in their discussion of potential mechanisms by which cancer might increase risk of stroke, which I think an oversight - senescent cells are known to influence many of the mentioned mechanisms. While much of the research community is embracing the contribution of cellular senescence to aging and age-related disease, there is still a way to go yet.

Stroke among cancer patients

We present a contemporary analysis of risk of fatal stroke among more than 7.5 million cancer patients and report that stroke risk varies as a function of disease site, age, gender, marital status, and time after diagnosis. The risk of stroke among cancer patients is two times that of the general population and rises with longer follow-up time. The relative risk of fatal stroke, versus the general population, is highest in those with cancers of the brain and gastrointestinal tract. The plurality of strokes occurs in patients older than 40 years of age with cancers of the prostate, breast, and colorectum. Patients of any age diagnosed with brain tumors and lymphomas are at risk for stroke throughout life.

Most cancer patients now die of non-cancer causes. The results of the current work suggest that stroke prevention strategies may be aimed at patients treated for brain tumors and lymphomas (particularly children) and older patients (i.e., older than 40 years) diagnosed with cancers of the prostate, breast, and colorectum. Though relatively less common, patients with cancers of the gastrointestinal tract (especially the pancreas, liver, esophagus) are at a relatively high risk to die of stroke at any time after diagnosis. We encourage individual guideline and survivorship committees to incorporate these data into their stroke prevention statements.

Relatively few studies have examined the risk of stroke among cancer patients, and the current analysis is the largest of its kind. Similar to previous analyses, we found that lung, prostate, breast, and colorectal patients experience the plurality of strokes. Although the current analysis does not include patient comorbidities or biomarkers, other studies suggest that D-dimer levels and classic risk factors for stroke (e.g., hypertension) put patients at greatest risk.

The risk factors for stroke in cancer patients are under investigation. A systemic review reported that patients with cancer are subject to the same stroke risk factors as the general population, and atherosclerosis remains the most common cause of stroke in cancer patients. Further, the authors noted that if stroke in cancer patients was caused by the same pathophysiologic mechanisms as in the general population, the distribution of stroke should be identical to the population at large, and there would be a distribution of primary neoplasms proportional to the most common cancers (i.e., lung, breast, and prostate). In their review, there was a relatively wide variability of stroke among tumor types.

Several pathways for increased risk of stroke in cancer patients have been proposed, and there are several cancer-specific types and causes of stroke in cancer patients. Cancer may lead to stroke via several mechanisms. First, certain cancers cause occlusive disease from emboli, compression, or meningeal extension of tumor. Tumor dissemination into the leptomeningeal space can lead to vascular compromise. Patients with leukemia and elevated leukocyte counts may develop intravascular leukostasis, leading to hemorrhagic infarct. Brain tumor metastases may also cause hemorrhage, and this is more common in cancers of the kidneys, thyroid, germ cells, melanoma, and choriocarcinoma. Second, coagulopathies, including non-bacterial thrombotic endocarditis (NBTE), may cause stroke. NBTE, or marantic endocarditis, is characterized by the presence of relatively acellular aggregates of fibrin and platelets attached to normal heart valves. Third, stroke may occur from therapy, such as radiation therapy-induced atherosclerosis, drug-induced thrombocytopenia, and hypercoagulability.

Calorie Restriction as a Way to Slow Harmful Age-Related Changes in the Gut Microbiome
https://www.fightagi...gut-microbiome/

The practice of calorie restriction, eating 20-40% fewer calories while still obtaining an optimal intake of micronutrients, produces sweeping changes in the operation of cellular metabolism. It improves health and extends life span in near all species tested to date, though much more so in short-lived species than in long-lived species. The most important mechanism appears to be a boost to the operation of the cellular housekeeping processes of autophagy, more efficiently clearing out damaged components and unwanted molecular waste before they can cause further issues. That said, near every measure of aging is slowed by calorie restriction, so it is no surprise to see in today's open access paper that this slowing also applies to the detrimental changes to the microbial populations of the gut that are observed to take place with age.

In recent years the research community has been giving ever more attention to the gut microbiome in the context of long-term health and aging. Gut microbes produce a number of compounds that are beneficial, such as tryptophan, indole, butyrate, and propionate, but this production falls off in adult life and into old age. Populations of beneficial bacterial species are replaced by populations of harmful species that interact with tissues and the immune system to cause chronic inflammation. There are many possible contributing causes for age-related changes microbial populations in the gut, such as specific dietary changes, as well as failure of the immune system to control harmful populations. It isn't clear as to which of these are more or less important, however.

While calorie restriction seems to slow this progression, and here again it is hard to say which of the possible mechanisms are the important ones, transplantation of gut microbes appears to be a better approach, one capable of reversing age-related changes. This has been demonstrated with fecal microbiota transplants from young animals to old animals, and this form of treatment is well proven in humans as a therapy for a range of conditions in which the gut is colonized by pathological microbes. It has also been trialed for a range of medical conditions that are suspected to have some inflammatory or other contribution arising from gut microbes, such as Parkinson's disease. So why not the condition of aging as well?

Calorie restriction slows age-related microbiota changes in an Alzheimer's disease model in female mice

The gut-brain axis is an integrated network in which the microbiota and central nervous system communicate via endocrine, immune, and neural signaling pathways. Several translational studies show that transferring microbiota from patients with neurodevelopmental and neurological disorders including autism, multiple sclerosis, and Parkinson's disease can influence behavior, motor dysfunction, and immune responses in relevant animal models. These studies provide evidence that intestinal microbiota may play an etiologic role in diseases that emerge at differing points during the lifespan. Consistent with this notion, Alzheimer's disease (AD) patients have altered gut microbiota compared to age-matched healthy subjects. In established animal models of AD, depleting the microbiota either in germ-free or antibiotic-treated mice served as protection against the pathological hallmark amyloid-beta (Aβ) plaque deposition.

While host genotypes influence AD risk, the most important risk factor is advanced age. In older adults, the microbiota is less diverse, and immunosenescence and age-related changes in host physiology can destabilize the microbiota. An 'aged' microbiota promotes immune dysfunction, including increased systemic inflammation and impaired macrophage phagocytosis, which can be partially restored by transferring microbiota from young to aged mice. Thus, understanding how to slow or reverse age-related changes in the gut microbiota has therapeutic implications for age-related brain diseases, including AD.

Diet is a major environmental factor that modulates the microbiota and has been proposed to prevent age-related changes of the microbiota. Calorie restriction (CR), characterized by 20-40% reduction of total calorie intake without malnutrition, increases the healthspan and lifespan in multiple model organisms. A 30% reduction in calories from carbohydrates activates neuroprotective signatures and suppresses age-related transcriptional changes in the hippocampus in wildtype (WT) mice. In the context of AD, we found that CR prevents Aβ plaque accumulation and modulates the expression of the gamma-secretase complex, the amyloid-beta precursor protein (APP) processing enzymes, in a sex-dependent manner in Tg2576 mice. In addition to effects on host physiology, CR modulates the microbiota and increases abundances of bacteria that positively correlate with lifespan. However, the association between CR, the microbiome, and AD pathogenesis has not been established.

In this study, we investigated the effect of long-term 30% CR compared with ad libitum (AL) feeding on the microbiome in aging. We studied the Tg2576 model, where a mutant variant of the human APP is expressed in transgenic mice. This transgene results in cerebral amyloid accumulation, synaptic loss, and cognitive impairment by 12 months of age. We found that female Tg2576 mice have more substantial age-related microbiome changes compared to wildtype (WT) mice, including an increase in Bacteroides, which were normalized by CR. Specific gut microbiota changes were linked to Aβ levels, with greater effects in females than in males. In the gut, Tg2576 female mice had an enhanced intestinal inflammatory transcriptional profile, which was reversed by CR. Furthermore, we demonstrate that Bacteroides colonization exacerbates Aβ deposition, which may be a mechanism whereby the gut impacts AD pathogenesis. These results suggest that long-term CR may alter the gut environment and prevent the expansion of microbes that contribute to age-related cognitive decline.

Ways in Which the Failing Lymphatic System Contributes to Age-Related Disease
https://www.fightagi...elated-disease/

The lymphatic system is a parallel circulatory system responsible for moving fluid, immune cells, and a range of vital molecules around the body. It is of particular importance to immune function, allowing components of the immune system to carry messages from place to place in the body, and communicate and coordinate the immune response at the hubs known as lymph nodes. Like all tissues in the body, the lymphatic system is negatively impacted by aging, and this has widespread detrimental effects throughout the body and brain.

For example, lymph nodes become disrupted in structure and function by the presence of senescent cells and consequent fibrosis as tissue maintenance runs awry in the face of the senescence-associated secretory phenotype. The consequences of this are well demonstrated in a recent paper: very old mice and primates suffering from immunosenescence, an immune system with a poor response to pathogens, cannot benefit from the addition of new, functional immune cells. Their lymph nodes are too structurally impacted to allow the new cells to coordinate an effective immune response. Given that fibrosis in a number of tissues has been reversed in animal models via use of senolytics to clear senescent cells and their inflammatory signaling, it is possible that lymph node aging might be reversed to some degree. If the structure cannot be regenerated, however, then there are efforts underway to produce artificial lymph nodes that can be transplanted to integrate with the lymphatic system.

It isn't just a matter of lymph nodes, of course. Lymphatic vessels actively pump their contents, and this pumping function declines and becomes erratic with advancing age. Other forms of degeneration also take place, impairing the ability of immune cells and their signals to move about the body. This is a harder problem to solve, given its distributed nature, and that it probably arises due to contributions from most of the underlying forms of molecular damage that cause aging. It is important for the research community to keep working on means of repair for all forms of damage, not just focus on the approaches, like senolytics, that are closest to practical clinical use.

Reduced lymphatic function contributes to age-related disease

The diverse etiologies of age-related diseases, from osteoarthritis to Alzheimer's disease, all share an impairment, or slow loss, of tissue function. Aging tissue homeostasis shifts towards progressive, low-grade inflammation and a dampened immune response. The lymphatic vasculature is the key regulator of tissue homeostasis in health and disease. Lymphatics transport antigens and other macromolecules, excess interstitial fluid, and activated immune cells during inflammation. Here we highlight how reduced lymphatic function is a key component regulating several age-related diseases.

Lymphatic vessels are structurally quite different from blood vessels, beginning with blind-ended capillaries possessing leaf-like cell junctions that lead to large, unidirectionally-valved collecting vessels. These larger vessels are surrounded by lymphatic muscle cells that provide intrinsic pumping to maintain lymph flow. A recent review focused on lymphatic collecting vessels found that lymphatic muscle contractions are reduced in amplitude and frequency and can become irregular with age. Other researchers have demonstrated altered muscle coverage and function, decreased ion channel activity, limited nitric oxide responsiveness, and reduced antigen trafficking in aged lymphatic vessels: all leading to an impairment of the immune response. They identified that increased mast cell investiture and elevated histamine levels cause heightened basal NF-kB activity in aged lymphatic vessels. This resulted in a blunted inflammatory response both in reduced vessel contractility and limited NF-kB activation. Tissue homeostasis depends on lymphatics and the structural and physiologic decline in lymphatic vessel function likely contributes to age-associated pathologies.

Chronic tissue degeneration is a common feature of age-associated disorders like osteoarthritis (OA). A series of collaborative studies have extensively detailed lymphatic involvement in several models of arthritis. Inflammatory lymphangiogenesis and increased pumping initially facilitate the removal of immune cells and fluid to the draining lymph nodes, but that over time lymphatics regress and collecting lymphatic vessels lose contractility. In their recent study of OA, blocking lymphangiogenesis accelerated joint tissue loss. The team identified increased pro-inflammatory macrophages in the knee joint and increased inflammatory markers expressed by lymphatic endothelial cells. Treatment with the proteasome inhibitor bortezomib was found to significantly improve lymphatic drainage and reduce cartilage loss. The group's arthritis research portfolio has clearly identified that maintaining effective lymphatic drainage reduces inflammation through fluid clearance and immunomodulatory mechanisms. Further elucidating these mechanisms may make modulating lymphatics a strategy to slow OA progression.

Cardiovascular (CV) disease and diabetes are progressive pathologies whose diagnoses increase with age, and the side effects, treatment, and recovery are more difficult to manage in older patients. Lymphatic vessels have demonstrated a critical role and therapeutic potential in several CV pathologies including atherosclerosis, myocardial infarction, hypertension, and diabetes. Atherosclerosis is characterized by chronic cholesterol-rich plaque accumulation and macrophage foam cell residency in the arterial wall. Preventing lymphangiogenesis worsened lesions while increasing lymphatics reduced macrophage numbers and cholesterol content, highlighting the lymphatic route of immune cell and macromolecule. Similarly, following myocardial infarction, functional lymphangiogenesis reduced fluid accumulation and inflammatory fibrosis. We recently demonstrated that the therapeutic induction of lymphangiogenesis specifically in the kidney may target the chronic renal inflammation characteristic of hypertension and prevent an elevation in blood pressure. Similarly, we found that inducing lymphangiogenesis in adipose tissue reduced adipose-associated macrophage accumulation and improved glucose homeostasis in an obese mouse model of diet-induced diabetes. Age-related lymphatic impairment may therefore provide a target to slow the functional decline of CV tissues.

Corpora Amylacea in the Clearance of Metabolic Waste from the Brain via Cerebrospinal Fluid Drainage
https://www.fightagi...fluid-drainage/

Age-related neurodegeneration is characterized by rising levels of various protein aggregates in the brain. A few of the many thousands of proteins in the body can become misfolded in ways that encourage other molecules of the same protein to also misfold in the same way, forming structures that spread and precipitate into solid deposits. These aggregates are accompanied by a halo of surrounding biochemistry that is toxic to neurons, disrupting function in the brain and killing vital cells, causing loss of cognitive function and ultimately death.

In recent years, increasing attention has been given to the role of cerebrospinal fluid drainage in maintaining the brain. The circulation of cerebrospinal fluid is not a closed system, but one that drains into the body via a few different routes. This is a path for molecular waste of all sorts to be removed from brain tissue, but unfortunately it deteriorates with age. The company Leucadia Therapeutics is founded on evidence for one such drainage path, through the cribriform plate, to become blocked with age, thereby leading to the early stages of Alzheimer's disease because amyloid-β cannot be cleared as rapidly as is needed. Similarly, other paths through the glymphatic system also deteriorate with age, for different reasons, and with similar consequences for the clearance of molecular waste.

Today's open access paper is of interest in this broader context. It examines one of the mechanisms by which waste can be packaged up into granules, exported from brain tissue into the cerebrospinal fluid, and thereby drained from the brain to be dealt with by immune cells elsewhere in the body.

Corpora amylacea act as containers that remove waste products from the brain

In 1837 the anatomist and physiologist J. E. Purkinje described the presence of some particular granular bodies in the brain of elderly patients. These bodies, named corpora amylacea (CA), were initially considered to have no pathological significance and for a long time were thought to be irrelevant. In recent decades, however, this perception has changed. With the advances in technology, CA have been studied from different perspectives and a large number of theories regarding their nature have been put forward. Unfortunately, none of these theories have been demonstrated conclusively and CA remain intriguing and mysterious bodies. In the present study, several features of CA are described and a vision of their function is proposed which may have implications for clinical practice.

There is a consensus that the main components of CA are polymerized hexoses (primarily glucose). Other components originating in neurons, astrocytes, or oligodendrocytes, from blood or of fungal or viral origin, have also been described. We observed that CA contain glycogen synthase (GS), an indispensable enzyme for polyglucosan formation, and also ubiquitin and protein p62, both associated with processes of elimination of waste substances. The relationship between CA and waste substances is recurrent in the literature. CA functions seem to be directed towards trapping and sequestration of potentially hazardous products of cellular metabolism, principally derived from the aging process, but probably also from any disease state resulting in excessive amounts of potentially harmful metabolic products.

It is well known that CA are located mainly in perivascular, periventricular, and subpial regions of the brain. Since the glymphatic system drains the interstitial fluid (ISF) from the perivascular regions to the cerebrospinal fluid (CSF), and since both periventricular and subpial regions are close to the cavities that contain the CSF (i.e., ventricles and subarachnoid space), it is plausible that CA are expelled from the brain to the CSF. The CSF drains not only via arachnoid granulations, as classically believed, but also via the recently rediscovered meningeal lymphatic system. From meningeal lymphatic vessels and subsequent lymphatic vessels, lymph crosses different cervical lymph nodes before accessing the lymphatic duct or right thoracic duct, which ultimately drain into the brachiocephalic veins.

On this basis, it has been reported that meningeal lymphatic vessels allow the brain to eliminate macromolecules by collecting them from the CSF. Conceivably, in the same way as waste molecules generated in the brain, it is possible that CA released from the brain into the CSF escape from the CSF via the meningeal lymphatic system, reaching the deep cervical lymph nodes or beyond. The lymphatic capillaries are formed by overlapping cells that can act as valves leaving relatively large openings, allowing the passage of macromolecules and even cells, and thus also the passage of CA. Overall, this evidence suggests a mechanism for eliminating residual substances from the brain in which CA act as waste containers that are extruded from the brain to the CSF. Afterward, via the meningeal lymphatic system, CA can reach the cervical lymph nodes, and macrophages located there may play a significant role in their phagocytosis.

This study shows that CA are released from periventricular and subpial regions to the cerebrospinal fluid and are present in the cervical lymph nodes, into which cerebrospinal fluid drains through the meningeal lymphatic system. We also show that CA can be phagocytosed by macrophages. We conclude that CA can act as containers that remove waste products from the brain and may be involved in a mechanism that cleans the brain. Moreover, we postulate that CA may contribute in some autoimmune brain diseases, exporting brain substances that interact with the immune system, and hypothesize that CA may contain brain markers that may aid in the diagnosis of certain brain diseases.

A Large Study of Aspirin Use Finds Reduced Mortality, Contradicting the Recent ASPREE Study Results
https://www.fightagi...-study-results/

The back and forth over whether regular aspirin use is beneficial continues with the publication of results from analysis of a large patient population that show a 15% reduction in all cause mortality in patients using aspirin. This contradicts the much smaller (but still large in and of itself) ASPREE clinical trial, in which patients using aspirin exhibited a small increase in mortality in comparison to their peers. As in that earlier study, the data here strongly suggests that benefits and risks vary with patient characteristics, such as whether or not a patient is overweight.

Aspirin is thought to be a weak calorie restriction mimetic, in that it can produce benefits via upregulation of autophagy to some degree, but it also reduces inflammation and blood clotting, among other effects. That reduction in inflammation is probably the most important benefit. Other studies suggest that the use of NSAIDs like aspirin reduces risk of Alzheimer's disease, which may well be the case for any long-term anti-inflammatory treatment, given the strong role played by chronic inflammation in that condition.

This sort of contradictory evidence is characteristic of medications with small effects. One would imagine that senolytics, capable of producing a larger and more reliable reduction of chronic inflammation in old people via clearance of senescent cells, could be put through much the same sort of clinical trials and emerge on the other side with far less ambiguity in the outcome for patients. We shall see whether or not this is the case in the years ahead, of course. But the point is that large effects tend to lead to consistent data, while inconsistent data is a hallmark of small effects.

Association of Aspirin Use With Mortality Risk Among Older Adult Participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

This cohort study found that aspirin use among individuals 65 years and older was associated with a lower risk of mortality. This observation was consistent across all causes of mortality, i.e., all-cause, cancer, gastrointestinal cancer, and colorectal cancer (CRC); however, the greatest reduction in risk was noted for CRC mortality among individuals who used aspirin 3 or more times per week. Additionally, our exploratory analyses investigating the potential associations among aspirin use, BMI, and mortality risk suggest that the efficacy of aspirin as a cancer preventive agent may be associated with BMI. Participants in the PLCO Cancer Screening Trial who were underweight (i.e., BMI less than 20) had no observable benefit associated with aspirin use, while those with BMI 20 or higher were associated with reduced mortality risk, particularly with aspirin use 3 or more times per week. reduced risk of CRC mortality was only associated with individuals with BMI 20 to 29.9 who reported aspirin use 3 or more times per week.

The efficacy of prophylactic aspirin use for prevention of cancer incidence and mortality has been debated; however, the most evidence from prospective cohorts and secondary analyses from clinical trials indicates a protective association with aspirin use. A 2016 systematic analysis of primary and secondary cardiovascular prevention trials found reduced CRC incidence 10 to 19 years after aspirin use initiation. This association persists among investigations of aspirin use and cancer mortality.

These observations are in contrast with data from the ASPREE trial. However, the interpretation of the ASPREE results is limited owing a lack of an association of aspirin with cancer and CRC incidence and the short duration of follow-up. With additional follow-up, an association of aspirin with lower cancer incidence and death may have emerged. In addition, a 2018 combined analysis of the NIH-AARP Diet and Health Study and the PLCO Cancer Screening Trial reported decreased risk of all-cause, cancer, and cardiovascular mortality associated with daily aspirin use. However, a dosage that exceeded 1 per day was associated with an increased risk of mortality. These data also did not account for effect modifications by BMI on mortality risk. Previous studies have also found that variables, such as BMI, are associated with the efficacy of prophylactic aspirin. In a 2012 study of the Cancer Prevention Study-II Nutrition Cohort, individuals with prediagnostic BMI 30 or higher were associated with increased risk of all-cause and CRC death. A similar association was demonstrated across several other cohort and case-control studies, cancers, and causes of death.

The observation that BMI may be associated with efficacy of aspirin in individuals 65 years and older is notable; however, our findings require further confirmation. Increasing rates of overweight and obesity globally may substantially alter the population-based efficacy of cancer prevention prophylatics. Studies have suggested that aspirin has reduced effectiveness as a primary prevention modality among individuals who are obese owing to decreased bioavailability and antithrombotic efficacy; however, this study did not find an association of overweight or obesity with decreased efficacy. Therefore, although aspirin use is associated with benefit as a cancer preventive agent, the changing characteristics of the global population may alter its efficacy and must be considered along with age and risk of bleeding before recommending aspirin for cancer prevention.

Low Lymphocyte Levels Correlate with Greater Mortality in Late Life
https://www.fightagi...y-in-late-life/

Lymphopenia is the condition of having lower than normal levels of lymphocytes, a mix of cells of the adaptive and innate immune system, in blood samples. The immune system is of vital importance to health, and this is demonstrated here by data that shows raised mortality in the sizable fraction of older people with degrees of lymphopenia versus those without. Lymophocytes do not just respond to the presence of infectious pathogens, but also attack and destroy senescent cells and cancerous cells, among other important activities. A severely deficient immune system is a real threat to life, and as this work illustrates, even a modestly deficient immune system is something to worry about.

The near future should see the advent of approaches to restore immune function in the elderly. Regrowth of the atrophied thymus, where T cells of the adaptive immune system are trained; restoration of the declining hematopoietic stem cell population responsible for creating immune cells in the bone marrow; clearance of harmful populations of misconfigured, senescent, and exhausted T cells in the aged immune system; regeneration of fibrotic and structurally disrupted lymph nodes. These four approaches, as they are enacted, should go a long way towards ensuring a healthier, longer life for older people.

This study sought to (1) determine the associations among lymphocyte levels, other immunohematologic parameters, and survival and (2) establish the extent to which the associated risk of these variables is additive. In this large cohort of adults, we found that lymphopenia was associated with mortality risk independently of traditional clinical risk factors and other immunohematologic variables (red blood cell distribution width and C-reactive protein level). Individuals with multiple immunohematologic abnormalities had a strikingly high risk of mortality among this generally low-risk population. Approximately 20% of the general US population appears to have a high-risk immunohematologic profile, and these participants' 10-year mortality was 28%, compared with 4% in participants in the present study with a low-risk profile. The risk associated with this immunohematologic pattern is independent of (and thus additive to) traditional clinical risk factors. Together, these data suggest that immunohematologic risk may be viewed as a multidimensional entity and can be estimated using markers commonly available as part of routine clinical care.

We believe the results presented herein add to the growing body of evidence that immune status is associated with cardiovascular and noncardiovascular disease. Previous observational and prospective trials suggest that participants with overt or subacute inflammatory diseases have elevated risk of atherothrombotic disease, heart failure, malignant disease, and death. Comparatively few studies have evaluated absolute lymphocyte count as a prognostic biomarker. Herein, we found that lymphopenia is relatively common in the general population and is associated with reduced longevity independently of age, clinical risk factors, and other immunohematologic parameters. In our fully adjusted analyses, a bimodal relationship between lymphocyte counts and mortality emerged, suggesting that the expansion of lymphocytes may also introduce hazard in the general population.

Because mortality in this population was largely driven by noninfectious causes, these data support the notion that immune status is indeed associated with resilience against cancer and cardiovascular disease, and an adverse immune phenotype may precede clinical manifestations of these illnesses. Whether lymphocyte levels are themselves part of the causal pathways linking lymphopenia to death will require additional study. Cytotoxic T cells can eradicate cells with malignant potential, and thus an optimal absolute lymphocyte count may reflect an immune system capable of providing protection against tumor development. Lymphopenia can also induce compensatory proliferation of antigen-experienced T cells, which could increase the risk of cardiovascular disease. In those with lymphocytosis, dysregulated expansion of memory T cells, whether driven by indolent viral infections (eg, cytomegalovirus) or other mechanisms, may induce a proinflammatory milieu and similarly elevate the risk of incident cardiovascular disease.

Lymphopenia may also reflect adverse inflammatory, metabolic, or neuroendocrine stressors and thus be associated with survival as an epiphenomenon. The administration of tumor necrosis factor, interleukin 1β, or microbial products reduces levels of circulating T cells. Excess levels of cortisol and catecholamine also cause lymphopenia. In these disease and models systems, lymphopenia was caused by redistribution of T cells from the circulation to lymphoid tissues and an increased susceptibility of T cells to apoptosis. Thus, additional study is needed to characterize the immune, metabolic, and neuroendocrine profiles in those with dysregulated T-cell homeostasis and to explore the lines of causation and effect that may contribute to resilience and longevity in the primary prevention setting.

Are Benefits from Cardiac Stem Cell Therapy Due to an Immune Response to Transplanted Cells?
https://www.fightagi...splanted-cells/

As this article notes, researchers have recently suggested that the benefits to heart function observed over many years of stem cell therapies are not in fact due to any action of the cells themselves, not even cell signaling mechanisms such as release of exosomes, but are rather due to an immune response to the transplanted cells. The study reported here illustrates the point by showing some degree of regeneration of injured heart tissue to take place in mice when the debris of dead cells is transplanted. We might compare these findings with the body of work showing that delivery of exosomes can spur cardiac regeneration; few portions of the field of stem cell therapy are lacking a good supply of contradictory evidence.

For 15 years, scientists have put various stem cells into seriously ill patients' hearts in hopes of regenerating injured muscle and boosting heart function. A new mouse study may finally debunk the idea behind the controversial procedure, showing the beneficial effects of two types of cell therapy are caused not by the rejuvenating properties of stem cells, but by the body's wound-healing response - which can also be triggered by injecting dead cells or a chemical into the heart.

The discovery will have to be repeated and investigated in human tissue, but the emergence of a likely explanation for how heart cell therapy can have modest benefits comes after years of hype, hope and disagreement about stem cells' potential to heal broken hearts. Experimental therapies have been tested in hundreds of patients with heart disease, even as doubts have grown about the underlying scientific rationale. The idea that the cells could regenerate the heart was intuitively attractive and captured a field searching for therapies to offer desperate patients, and many scientists started companies to try to commercialize different cell types. The new work provides a long-awaited explanation - one that some outside scientists argued does not support more trials with the cells.

Five years ago, researchers debunked the idea that one type of heart stem cell, called a cardiac progenitor cell, was a stem cell at all. Contrary to expectations, those cells were not regenerating appreciable amounts of heart muscle after being injected into injured mouse hearts. Some scientists and physicians, many of whom had built careers on the use of cells as therapy, argued that it wasn't the cells themselves doing the repair but, rather, factors that the cells secreted. In the new study, scientists reported that the modest beneficial effects of injecting either cardiac progenitor cells or bone marrow cells into the injured mouse heart don't appear to be specific to the cell therapy. Modest improvements in heart function, the result of the healing of a heart attack scar, can also be triggered by injecting dead cellular debris or a chemical that stimulates the immune system.

"The progression, after we figured out that was wrong, was that people were hoping the cells we inject make a magic soup ... that revitalize the cells. What we did and showed is there is no magic soup. You're injecting cells, they're dying and stimulating an immune response."

Investigating Circular RNAs in Cellular Senescence
https://www.fightagi...lar-senescence/

Numerous demonstrations of rejuvenation via clearance of senescent cells in recent years have led to a newfound and considerable enthusiasm for the study of the mechanisms of cellular senescence. Ever more funding in flowing into this part of the life sciences. That any new discovery might lead to a company, valuable intellectual property, a means to treat aging, is a considerable incentive forthe various research and funding ecosystems. The open access research noted here is a representative example of numerous projects presently underway.

Cellular senescence is involved in modulating aging and aging-associated pathologies via the senescence-associated secretory phenotype (SASP). Growing evidence has implicated the accumulation of senescent cells are implicated in chronologic aging of organisms. Several lines of evidence have suggested that cellular senescence is closely associated with age-related diseases. Therefore, characterizing the regulatory mechanisms of cellular senescence may allow us to intervene in aging-related diseases.

Circular RNAs (CircRNA) generated by back-splicing are highly conserved and stable long non-coding RNAs abundant in eukaryotic transcriptomes. Currently, the functions of most CircRNAs remain largely unexplored; however, the known functions include (I) sequestration of microRNAs or proteins; (II) modulation of transcription and splicing; (III) peptide or protein encoding. CircRNAs are also involved in various pathological and physiological processes, including cancer development, cardiovascular disease, and aging. However, molecular mechanisms and functions of CircRNAs in cellular senescence and aging of organisms remain largely unknown.

The present study identified senescence-associated CircRNAs (SAC-RNAs) by the whole-transcriptome sequencing, and revealed that CircCCNB1 is dramatically downregulated in replicative senescence and prematurely senescent fibroblasts. Short hairpin RNA (shRNA)-induced knockdown of circular cyclin B1 (CircCCNB1) led to senescence in proliferating fibroblasts. Mechanistically, CircCCNB1 regulated cyclin E2 (CCNE2) by controlling microRNA 449a (miR-449a) activity. Our data implicated that CircCCNB1-miR-449a-CCNE2 axis in the regulation of cellular senescence. Modulating miRNA activity by targeting SAC-RNAs can influence target protein expression, which may represent a promising strategy for aging and age-related disease interventions.

Proteasomal Failure as a Contributing Cause of Protein Aggregation in Neurodegenerative Disease
https://www.fightagi...rative-disease/

Neurodegenerative diseases are characterized by the formation of protein aggregates, misfolded proteins that encourage other molecules of the same protein to also misfold in the same way, forming solid deposits that damage and destroy brain cells. Researchers here suggest that the age-related decline in proteasomal function is a contributing factor. The proteasome is a structure that breaks down damaged or otherwise unwanted proteins in cells. While this form of cellular housekeeping does decline with age, and there is good evidence in lower animals for increased proteasomal function to slow aging, it is worth bearing in mind that the research here is based on deliberately breaking proteasomes by removing a crucial component protein. It is always difficult to say whether the results of this sort of breakage are relevant to aging - it strongly depends on the details in each case.

Proteasomes are made in the cell body of a neuron and need to be transported over long distances to reach the nerve endings where the neuron connects with other cells - a journey of more than one meter in some cases. When proteasomes fail to reach these critical communication hubs, the cell descends into turmoil. Instead of being degraded, damaged proteins in these sites hang around long enough to interact with other binding partners, form aggregates, and disrupt cell function. Over time, this causes degeneration of nerve fibers and ultimately cell death.

When researchers began investigating the proteasome transportation system in fruit flies, they identified a protein called PI31, which plays a crucial role in loading the proteasomes onto the cellular components that ferry them around. They show that PI31 enhances binding and promotes movement of proteasomes with cellular motors. Without it, transport is halted. This is the case in both fly and mouse neurons, suggesting that the transport mechanism is common between many species. Digging deeper into what happens when PI31 is defective, the scientists generated mice whose PI31 gene was switched off in two groups of brain cells with particularly long extensions. They found that without PI31, proteasomes cannot travel, resulting in abnormal protein levels at the tips of neuronal branches. The PI31-lacking neurons also looked peculiar, both with respect to their branches and to their synapses, the structures where branches from two neurons connect. Notably, these structural changes became progressively more severe with age.

There are other reasons to suspect that the lab's findings could inform the treatment of neurodegenerative diseases. For example, mutations in the PI31 gene have been linked to Alzheimer's disease. The fact that PI31 appears to be involved in the early stages of nerve cell degeneration is especially compelling, as it could mean that drugs blocking this protein might have the potential to halt brain damage early on in the process. The researchers believe the formation of aggregates is likely not the direct disease mechanism, but rather a symptom of bigger problems. "Our work suggests that it really starts with a local defect in proteasomes, resulting in the failure to degrade proteins that are critical for nerve function. These undigested proteins subsequently form aggregates and activate additional damage control pathways. But eventually, these clearance systems are overwhelmed, which causes a slow but steady progression to a detectable disease."

Reviewing the Present Development of Biomarkers of Aging
https://www.fightagi...rkers-of-aging/

As this open access paper notes, a great deal of the present work on developing biomarkers of aging involves machine learning. Researchers are sifting and arranging health metrics, blood markers, and epigenetic data to find combinations that predict risk of disease and mortality. The aim at the end of the day is to determine a good measure of biological age, one that accounts for all of the burden of cellular and molecular damage that leads to death and dysfunction, and will thus be a good, rapid measure of effectiveness for rejuvenation therapies. The biggest challenge in this line of work at the present time is that researchers don't have a good understanding of what exactly is being measured by many of these potential biomarkers. It is entirely plausible that they are only a measure of some types of the underlying damage of aging, and will thus be of no use in assessing many of the possible approaches to rejuvenation.

The recent hype cycle in artificial intelligence (AI) resulted in substantial investment in machine learning and increase in available talent in almost every industry and country. This wave of increased attention to AI was fueled by the many credible advances in deep learning that allowed machines to outperform humans in multiple tasks. The advantage of deep learning (DL) systems is in their ability to learn and generalize from a large number of examples. DL methods rapidly propagated into the many biomedical applications, starting primarily with the imaging, text, and genomic data. The availability of large volumes of data and new algorithms made it possible to use deep learning to start making predictions about the activity and pharmacological properties of small molecules, identify mimetics of the known geroprotectors, and discover new ones.

There are many biological features that demonstrated correlation with the chronological age such as telomere length, racemization of amino acids in proteins, and others. The epigenetic age predictors were proposed in 2011. But it was not until 2012 when the first epigenetic aging clock was published by Hannum. Hannum's group profiled the methylomes derived from peripheral blood samples of healthy individuals to develop the first epigenetic clock consisting of 71 CpG sites and demonstrated the root mean squared error of 4.9 years on independent data. A more precise and comprehensive multi-tissue aging clock was then published in 2013 by Horvath who coined the terms "DNAm clock" and "epigenetic aging clock" and rapidly gained popularity in the aging research community. Horvath used 353 CpG sites and achieved a median error of 3.6 years on the testing set. These clocks were developed using traditional machine learning approaches - notably linear regression with regularization and the use of a limited number of samples. Similar methylation aging clocks were developed for mice.

With the first deep-neural-network-based aging clocks published in 2016, significant progress has been made the past few years in deep learned biomarkers of human aging. The first DL clock was constructed using 41 blood test values of over 50,000 individuals. Making use of deep neural network abilities to capture nonlinear dependencies between input data and target variable, the initially proposed method was able to achieve mean absolute accuracy of 5.5 years on previously unseen 12,000 individuals. Additionally, this study demonstrated how the deep clock can be used for further interpretations of relations between aging and blood parameters. By employing feature importance analysis they identified top parameters related to age changes.

The deep biomarkers of aging and longevity have a broad range of applications in research and development, medical, insurance, and many other areas. Developing comprehensive granular multi-modal aging clocks will help obtain a better understanding of the aging processes, establish causal relationships, and identify preventative and therapeutic interventions. One of the many promising applications of the deep aging clocks built into the generative adversarial networks is generation of synthetic biological data with age as a generation condition. The deep aging clock research is expected to increase in popularity.

A Survey of Existing Literature on Senescent Cell Burden by Age and Tissue in Humans
https://www.fightagi...ssue-in-humans/

Cells enter a state of senescence in response to reaching the Hayflick limit, or to a toxic environment, or potentially cancerous mutational damage. Near all senescent cells self-destruct, or are destroyed by the immune system. Some linger, however, and when present in even comparatively small numbers relative to normal cells, these senescent cells cause considerable harm via their inflammatory secretions. Thus the targeted destruction of senescent cells via senolytic therapies has been shown to extend healthy life and reverse numerous aspects of aging in mice. Human trials of senolytic treatments are presently underway, and have produced promising initial results.

Researchers here do the public service of combing through the existing literature on senescent cells in aging to assemble in one place all that is presently known on the level of cellular senescence in humans by age and tissue type. The data is fairly consistent, in that rising numbers of senescent cells with age appear throughout the body, but present techniques for assessing senescence clearly need to be improved, given that the numbers vary by measurement strategy.

This is the first study to quantify the association between the magnitude of senescence and chronological age across different human tissue types. A qualitative analysis of the literature identifies a largely positive association between cellular senescence and chronological age; however, the strength of the association differed based on the tissue type, subsection of tissue, and the senescence marker used within and between tissues. The observed differences in the strength of the association between senescence and chronological age between tissue types may be explained by the natural cell turnover rate of tissue which is known to vary widely. However, a tissue-specific response to environmental exposures or different defense mechanisms against cytotoxic stress may also explain this variable senescence level within human tissue types. For example, researchers demonstrated higher numbers of senescent cells in patients who have received chemotherapy.

To date, there is little data available on senescence within different organ systems from the same individual. Articles included in this review that investigated the difference in senescence within tissues of the same organ showed that despite higher senescence within these tissues, the magnitude of senescence differed based on the tissue or cell type. Researches also investigated senescence within individuals using tissue samples from different organs (blood and gut) and demonstrated that the magnitude of senescence was not only variable depending on the tissue assessed but also the marker used to define senescence. Thus, in alignment with the findings of this review, the current evidence would suggest that while cellular senescence is likely to increase with chronological age, the magnitude of senescence can vary from tissue to tissue. How this variation in senescence contributes to the onset of age-related disease is yet to be determined.

This analysis did identify some tissue types (adipose, gut, prostate, and thymus) where senescence was not significantly associated with age. The lack of significance in these tissues could be caused by the limited number of studies investigating senescence and age within these tissues and the smaller sample sizes within these articles. Thus, despite positive correlations the relationship between senescence and age within these tissues requires confirmation through additional studies. On the other hand, adipose and thymus tissue are also postmitotic tissue. Senescence within postmitotic cells, such as neurons, adipose, and skeletal muscle, has been largely overlooked in human research, which is reflected in this current review. This is likely due to a lack of evidence as to whether postmitotic cells can become senescent.

In addition to heterogeneity of senescence between and within tissue samples, senescence varied widely depending on the marker used to detect senescence. Notably, correlation of senescence markers and age differed substantially for proliferation and DNA damage markers. This is thought to be caused by the various other cellular processes these markers are involved in, as proliferation and DNA damage are not specific to the senescent phenotype. Furthermore, production of SA-β-gal does not necessarily indicate senescence either: quiescent cells in culture are also known to express SA-β-gal. Thus, the higher expression of any senescent marker within tissue samples as evidence of senescence must be viewed with caution. These observations are supported here by the pronounced heterogeneity of senescence within the same tissue sample, such as skin and eye, using different senescence markers.

Variation in Early Life Stress Contributes to Differences in Lifespan in Genetically Identical Worms
https://www.fightagi...dentical-worms/

Why do genetically identical nematode worms raised in the same environment exhibit a distribution in life span? Researchers here suggest that differences in oxidative stress in early life are an important contributing factor, perhaps steering metabolism in some of these simple organisms towards greater resistance to the rising oxidative stress of aging. So a form of hormetic effect, perhaps. Does this have much relevance to higher animals such as our own, however?

It would be challenging to separate out early life effects of this nature from the environmental differences across the whole of life, given the existing human epidemiological data. We might consider lines of research into childhood exposure to persistent viruses such as cytomegalovirus, which hint at an earlier burden of infection leading to a shorter and less healthy later life. Or evidence for greater exposure to solar radiation in utero, via seasonal variation, to produce differences in long-term human health and life expectancy. These are not hormetic effects, but ones in which the burden of increased damage reduces health and longevity. Perhaps hormetic effects do exist, but they would certainly be harder to find in the human data.

Oxidative stress happens when cells produce more oxidants and free radicals than they can deal with. It's part of the aging process, but can also arise from stressful conditions such as exercise and calorie restriction. Examining a type of roundworm called C. elegans, scientists found that worms that produced more oxidants during development lived longer than worms that produced fewer oxidants. Researchers have long wondered what determines variability in lifespan. One part of that is genetics: If your parents are long-lived, you have a good chance for living longer as well. Environment is another part.

That other stochastic factors might be involved becomes clear in the case of C. elegans. These short-lived organisms are a popular model system among aging researchers in part because every hermaphroditic mother produces hundreds of genetically identical offspring. However, even if kept in the same environment, the lifespan of these offspring varies to a surprising extent. "If lifespan was determined solely by genes and environment, we would expect that genetically identical worms grown on the same petri dish would all drop dead at about the same time, but this is not at all what happens. Some worms live only three days while others are still happily moving around after 20 days. The question then is, what is it, apart from genetics and environment, that is causing this big difference in lifespan?"

Researchers found one part of the answer when they discovered that during development, C. elegans worms varied substantially in the amount of reactive oxygen species they produce. Reactive oxygen species, or ROS, are oxidants that every air-breathing organism produces. ROS are closely associated with aging, but instead of having a shorter lifespan, worms that produced more ROS during development actually lived longer. When the researchers exposed the whole population of juvenile worms to external ROS during development, the average lifespan of the entire population increased. Though the researchers don't know yet what triggers the oxidative stress event during development, they were able to determine what processes enhanced the lifespan of these worms.

By separating worms that produced large amounts of ROS from those that produced little amounts of ROS, she showed that the main difference between the two groups was a histone modifier, whose activity is sensitive to oxidative stress conditions. The researchers found that the temporary production of ROS during development caused changes in the histone modifier early in the worm's life. How these changes persist throughout life and how they ultimately affect and extend lifespan is still unknown. What is known, however, is that this specific histone modifier is also sensitive to oxidative stress sensitive in mammalian cells. Additionally, early-life interventions have been shown to extend lifespans in mammalian model systems such as mice.

Assessing Late Life Cardiovascular Risk from Mid-Life Cholesterol Levels
https://www.fightagi...esterol-levels/

Researchers here use data on cholesterol and health assessed in a large patient population over a 40 year period in order to determine how the risk of suffering atherosclerosis by age 75 varies with cholesterol levels assessed in the 30s and 40s. It is no surprise that higher cholesterol levels mean a greater risk of atherosclerosis, the development of fatty lesions that narrow and weaken blood vessels. The condition is one in which the macrophage cells responsible for removing these unwanted lipids from blood vessel walls are made dysfunctional by rising levels of oxidized cholesterol. The more cholesterol in the blood stream, the more oxidized cholesterol, all other things being equal.

Using data for individuals without prevalent cardiovascular disease, we characterised the age-specific and sex-specific long-term association of non-HDL cholesterol with cardiovascular disease. On the basis of this association, we derived and validated a tool specific for age, sex, and cardiovascular risk factors to assess the individual long-term probability of cardiovascular disease by the age of 75 years associated with non-HDL cholesterol. Further, we modelled the potentially achievable long-term cardiovascular disease risk, assuming a 50% reduction of non-HDL cholesterol.

Considerable uncertainty exists about the extent to which slightly increased or apparently normal cholesterol concentrations affect lifetime cardiovascular risk and about which thresholds should be used to merit a treatment recommendation, particularly in young people. Our study extends current knowledge because it suggests that increasing concentrations of non-HDL cholesterol predict long-term cardiovascular risk, particularly in cases of modest increase at a young age.

Results showed a stepwise increase of cardiovascular disease events across increasing concentrations of non-HDL cholesterol. 30-year cardiovascular disease event rates were approximately three-to-four times higher in women and men in the highest non-HDL cholesterol category (≥5.7 mmol/L) than those in the lowest category (less than 2.6 mmol/L; 33.7% vs 7.7% in women and 43.6% vs 12.8% in men). To estimate the long-term probability of a cardiovascular disease event associated with non-HDL cholesterol, we established a model for cardiovascular disease risk up to the age of 75 years. For example, women with non-HDL cholesterol concentrations between 3.7 and 4.8 mmol/L, younger than 45 years, and with at least two additional cardiovascular risk factors had a 15.6% probability of experiencing a non-fatal or fatal cardiovascular disease event by the age of 75 years (28.8% in men with the same characteristics).

We calculated the optimally achievable risk reduction for cardiovascular disease by the age of 75 years assuming a 50% reduction of non-HDL cholesterol. In the population with non-HDL cholesterol of 3.7-4.8 mmol/L, younger than 45 years, and with at least two risk factors, the long-term risk of cardiovascular disease could hypothetically be reduced from 15.6% to 3.6% in women and from 28.8% to 6.4% in men. Absolute risk reductions of cardiovascular disease were more pronounced in individuals with two or more cardiovascular disease risk factors than in those with one or no risk factors, and in men than women.

Clearance of Senescent Cells is Fast in Youth, Slow in Aging, Tipping the Balance Towards Accumulation
https://www.fightagi...s-accumulation/

The accumulation of senescent cells is a cause of aging, which is why a great deal of effort is presently going towards the development of senolytic therapies capable of selectively destroying these unwanted cells. Very little is known about the dynamics of senescent cells in old age, however. We know that older individuals have more senescent cells at any given moment in time, but is this because a small fraction of the many senescent cells created every day manage to linger persistently for years, resistant to the efforts of the immune system to remove them, or because clearance processes, while they will eventually destroy all senescent cells, are slowed to the point at which they cannot keep up? This open access paper suggests the second option to be more plausible. This has implications for therapies, such as how often a senolytic treatment would need to be applied.

In this study, we propose a framework for the dynamics of senescent cell (SnCs) based on rapid turnover that slows with age. Bleomycin-induced SnC half-life is days in young mice and weeks in old mice, causing critical slowing down, which greatly amplifies the differences between individual SnC levels at old age. We theoretically explore the implications of this slowdown in a model in which SnCs cause death when they exceed a threshold. The widening variation in SnC levels with age causes a mortality distribution that follows the Gompertz law of exponentially increasing risk of death.

The rapid removal of SnCs that we observe following bleomycin-induced DNA damage is in line with studies that showed efficient removal of SnCs in vivo following liver fibrosis or induction by senescence by mutant Ras. On the other hand, when senescence was induced in the skin by directly activating the cell-cycle inhibitor p14ARF, which was not associated with an increase in tissue cytokine expression or inflammation, the induced SnCs persisted in the tissue for several weeks. Clearance may thus depend on the tissue, on the method of senescence induction, and on the presence of the senescence-associated secretory phenotype (SASP).

The present analysis of longitudinal p16 trajectories suggests that SnC slow down their own removal rate. This effect may be due to several mechanisms, including SASP, disruption of tissue architecture, or SnC abundance exceeding immune capacity. For the latter effect, SnC abundance at old age needs to be comparable to the abundance of the immune cells that remove them, which make up on the order of 0.1% of the body's cells. Further research is needed to characterize these effects.

Our results suggest that treatments that remove SnCs can therefore have a double benefit: an immediate benefit from a reduced SnC load, and a longer-term benefit from increased SnC removal. Similarly, interventions that increase removal capacity, for example by augmenting the immune surveillance of SnC, are predicted to be an effective approach to reduce SnC levels. More generally, the present combination of experiment and theory can be extended to explore further stochastic processes in aging, in order to bridge between the population-level and molecular-level understanding of aging.

A Review of Efforts to Target Senescent Cells in Order to Treat Age-Related Disease
https://www.fightagi...elated-disease/

This review paper looks at the present range of strategies adopted by the research and development communities in their efforts to target senescent cells. The accumulation of senescent cells is a contributing cause of aging; many animal studies have demonstrated reversal of aspects of age-related disease via clearance of senescent cells, particularly for those conditions in which chronic inflammation plays an important role. Senescent cells are comparatively few in number even in later life, but cause harm via secreted signals, a potent mix of proteins and vesicles known as the senescence-associated secretory phenotype (SASP). The SASP drives inflammation, changes the behavior of nearby cells for the worse, and destructively remodels surrounding tissue.

As there is ample evidence placing senescent cells as one of the causes of age-related dysfunctions, it has been considered to be one of the hallmarks of aging. It was recently demonstrated that elimination of senescent cells by genetic or pharmacological approaches delays the onset of aging-related diseases, such as cancer, neurodegenerative disorders, or cardiovascular diseases, among others, showing that the chronic presence of these cells is not essential. Conversely, local injections of senescent cells drive aging-related diseases. This data, together with that obtained from tissues of patients with different diseases and ages, has established causality of senescent cells in some aging-related pathologies.

One option to eliminate the negative effects of chronic senescent cells is to kill them specifically, using compounds called senolytics, which target pathways activated in senescent cells. The list of these senolytic compounds is extensive and continuously growing Senolytics target key proteins mainly involved in apoptosis, such as Bcl-2, Bcl-XL, p21, PI3K, AKT, FOXO4, and p53. Although senolytics are supposed to be specific for senescent cells, there are always unwanted damage/side effects since the administration is not directed. In this regard, a new strategy has been recently described to specifically target senescent cells in mice, using nanocapsules containing toxins (or senolytics). The outer layer of these nanocapsules are composed of substrates for enzymes that are overexpressed in senescent cells. In this way, the toxin (senolytic) will only be released inside senescent cells, killing them.

Another strategy to inhibit the functions of senescent cells is through the specific silencing of SASP, the complex mixture of soluble factors such as cytokines, chemokines, growth factors, proteases, and angiogenic factors that mediates the paracrine and autocrine functions of senescent cells. Senomorphics inhibit SASP functions by targeting pathways such as p38 mitogen-activated protein kinase (MAPK), NF-κB, IL-1α, mTOR, and PI3K/AKT, which act at the level of transcription, translation, or mRNA stabilization. Alternatively, inhibition may be achieved by specific antibodies against individual SASP factors (protein function inhibition), as is the case for IL-1α, IL-8, and IL-6. One doubt about this strategy is how SASP-silenced/attenuated senescent cells would be cleared. Given that some SASP factors are involved in the recruitment of immune cells, SASP inhibition could make senescent cells effectively "invisible" to the immune system, therefore remaining chronically within the tissue.

A third strategy to target senescent cells is to strengthen the immune system for efficient recognition and elimination of these cells, a process termed immunosurveillance. The role of the immune system in the elimination of senescent cells is fundamental, and a decline in immune function is associated with an increase in the number of senescent cells and finally, disease. In this regard, there are two strategies: i) improving the specific anti-senescent cell functions; and ii) general enhancement of immune functions (to avoid senescence of immune cells involved in recognition of senescent cells). Anti-senescent cell functions have been described in NK cells, macrophages, and CD4+ T cells. Since these functions take place through membrane receptors, one option is to increase the binding affinity of the involved receptors. In this sense, the use of chimeric antigen receptor (CAR) T cells to target specific senescent-related molecules would be an attractive approach.


View the full article at FightAging




0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users