Fight Aging! Newsletter, July 15th 2019

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  • Rate of Telomere Shortening Correlates with Species Average Life Span
  • More Supporting Evidence for Pancreatic Fat to be the Cause of Type 2 Diabetes
  • Both Extracellular Vesicles and Secreted Proteins can Spread Cellular Senescence
  • Telomere Dynamics with Age are Very Different Between Mammalian Species
  • The Question of a Limit to Human Life Span
  • Inducing the Heat Shock Response as a Potential Treatment for Atherosclerosis
  • Becoming More Physically Active in Middle Age or Later in Life Improves Longevity
  • A Potential Approach to Reducing TDP-43 Proteopathy in the Aging Brain
  • Vascular Calcification and Inflammation in Chronic Kidney Disease
  • OncoSenX Raises 3 Million to Adapt the Oisin Biotechnologies Platform to Cancer
  • Applying Bacterial Homing Strategies to Target Stem Cells to Heart Tissue
  • Reviewing Resistance Training as an Intervention to Reduce Chronic Disease Risk
  • Quiescence of Stem Cells in Aging as a Double Edged Sword
  • Aging is Accompanied by a Systemic Downregulation of Long Transcripts
  • Killer T Cells Invade the Aging Brain and Disrupt Generation of New Neurons

Rate of Telomere Shortening Correlates with Species Average Life Span

Researchers here report on data showing a correlation between species life span and pace of telomere shortening. Telomeres are the repeated DNA sequences at the ends of chromosomes. A little is lost with each cell division, during replication of DNA, and cells with very short telomeres become senescent or self-destruct. This is how the vast majority of cells in the body are limited in their replicative capacity, in order to lower the risk of damaged cells becoming cancerous to an evolutionarily acceptable level. Not a personally acceptable level, of course.

With age, average telomere length tends to shorten in most species, and this is most likely a reflection of loss of stem cell function. Stem cells maintain long telomeres via use of telomerase, and thus the daughter somatic cells they provide to support surrounding tissue also have long telomeres. Given fewer such daughter cells, average telomere length diminishes, along with tissue function - but that loss of telomere length isn't the cause of loss of tissue function.

Nonetheless, telomerase gene therapy extends life in mice, most likely by inducing damaged cells to greater activity in tissue maintenance. Since the immune system is most likely improved as well, this treatment doesn't lead to a greater incidence of cancer, which would be the usual outcome of making damage cells do more work. This hypothesis on what takes place in telomerase gene therapy is still not a suggestion that telomere shortening is a cause of aging. In this view telomerase gene therapy is conceptually similar to stem cell therapies or signaling therapies that increase native cell activity without repairing the underlying damage that caused the decline. As noted in the publicity materials, this particular research group is generally in favor of the opposite viewpoint, that telomere shortening is an important causative mechanism of aging, rather than a largely downstream reflection of other issues.

Researchers discover that the rate of telomere shortening predicts species lifespan

After analyzing nine species of mammals and birds, researchers found a very clear relationship between the lifespan of these species and the shortening rate of their telomeres, the structures that protect the chromosomes and the genes they contain. The fit is better when using the average lifespan of the species - 79 years in the case of humans - rather than the maximum lifespan -the 122 documented years lived by the Frenchwoman Jeanne Calment.

Until now, however, no relationship had been found between telomere length and lifespan of each species. There are species with very long telomeres that are short-lived and vice versa. The researchers decided not to compare the absolute length of the telomeres, but rather their rate of shortening. It is the first large-scale study that compares this highly variable parameter between species: human telomeres lose on average about 70 base pairs - the building blocks of the genetic material - per year, whereas those of mice lose about 7,000 base pairs per year.

"This study confirms that telomeres play an important role in aging. There are people who are not convinced, and they say that for example mice live two years and have very long telomeres, while humans live much longer and have short telomeres; but we have shown that the important thing is not the initial length but the rate of shortening and this parameter predicts the longevity of a species with a high degree of precision."

Telomere shortening rate predicts species life span

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin's gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus).

We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

More Supporting Evidence for Pancreatic Fat to be the Cause of Type 2 Diabetes

Type 2 diabetes is, for the vast majority of patients, a condition caused by being significantly overweight. Age does has an influence on the risk of being overweight leading to metabolic syndrome and then type 2 diabetes; it is reasonable to say that type 2 diabetes is an age-related condition. In essence, the younger you are, the more fat tissue it requires to push your metabolism over the red line. A few years back, researchers demonstrated that it is specifically fat in the pancreas that causes type 2 diabetes. Of course the only way to put that fat into the pancreas in the normal course of affairs is to become very overweight, creating fat tissue around all of the organs important to metabolism, and negatively influencing their function.

Now, a few years down the line, and as a result of the rapid growth of interest in senescent cells as a cause of aging and age-related disease, we know that (a) excess visceral fat tissue produces chronic inflammation through, among other mechanisms, a more rapid generation of senescent cells, and (b) much of the detrimental effects of type 2 diabetes appear to be mediated by the presence of senescent cells in the pancreas. Treating animals with senolytic drugs reverses many of the effects of the condition. So this all ties together quite nicely as a view of how and why type 2 diabetes occurs. Given that cellular senescence becomes more prevalent in older individuals, that also fits.

While I'm sure that there will be, soon enough, tremendous interest in senolytic therapies from the sizable overweight and diabetic population of the wealthier portions of the world, it remains the case that the most reliable approach to reversing type 2 diabetes, even at the later stages, is to lose the excess weight. Excess visceral fat tissue is required to maintain that harmful fat in the pancreas, and losing weight removes it. Fasting and very low calorie diets also seem quite effective at removing fat from the pancreas, perhaps more rapidly than would occur just by losing the visceral fat tissue via the usual, slow calorie deficit method, based on human trials of this approach.

Promising approach: Prevent diabetes with intermittent fasting

Fatty liver has been thoroughly investigated as a known and frequently occurring disease. However, little is known about excess weight-induced fat accumulation in the pancreas and its effects on the onset of type 2 diabetes. Researchers have now found that overweight mice prone to diabetes have a high accumulation of fat cells in the pancreas. Mice resistant to diabetes due to their genetic make-up despite excess weight had hardly any fat in the pancreas, but instead had fat deposits in the liver.

The team of scientists divided the overweight animals, which were prone to diabetes, into two groups: The first group was allowed to eat ad libitum - as much as they wanted whenever they wanted. The second group underwent an intermittent fasting regimen: one day the rodents received unlimited chow and the next day they were not fed at all. After five weeks, the researchers observed differences in the pancreas of the mice: Fat cells accumulated in group one. The animals in group two, on the other hand, had hardly any fat deposits in the pancreas.

In order to find out how fat cells might impair the function of the pancreas, researchers isolated adipocyte precursor cells from the pancreas of mice for the first time and allowed them to differentiate into mature fat cells. If the mature fat cells were subsequently cultivated together with the Langerhans islets of the pancreas, the beta cells of the islets increasingly secreted insulin. "We suspect that the increased secretion of insulin causes the Langerhans islets of diabetes-prone animals to deplete more quickly and, after some time, to cease functioning completely. In this way, fat accumulation in the pancreas could contribute to the development of type 2 diabetes."

Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice

Ectopic fat accumulation in the pancreas in response to obesity and its implication on the onset of type 2 diabetes remain poorly understood. Intermittent fasting (IF) is known to improve glucose homeostasis and insulin resistance. However, the effects of IF on fat in the pancreas and β-cell function remain largely unknown. Our aim was to evaluate the impact of IF on pancreatic fat accumulation and its effects on islet function.

New Zealand Obese (NZO) mice were fed a high-fat diet ad libitum (NZO-AL) or fasted every other day (intermittent fasting, NZO-IF) and pancreatic fat accumulation, glucose homoeostasis, insulin sensitivity, and islet function were determined and compared to ad libitum-fed B6.V-Lepob/ob (ob/ob) mice. To investigate the crosstalk of pancreatic adipocytes and islets, co-culture experiments were performed.

NZO-IF mice displayed better glucose homeostasis and lower fat accumulation in both the pancreas (-32%) and the liver (-35%) than NZO-AL mice. Ob/ob animals were insulin-resistant and had low fat in the pancreas but high fat in the liver. NZO-AL mice showed increased fat accumulation in both organs and exhibited an impaired islet function. Co-culture experiments demonstrated that pancreatic adipocytes induced a hypersecretion of insulin and released higher levels of free fatty acids than adipocytes of inguinal white adipose tissue.

Both Extracellular Vesicles and Secreted Proteins can Spread Cellular Senescence

The accumulation of senescent cells with age is one of the root causes of aging. Senescent cells never amount to more than a few percent of all cells, even in late life, but they secrete a mix of extracellular vesicles and various proteins that is inflammatory and disruptive to tissue function. This is known as the senescence-associated secretory phenotype, or SASP. Since senescent cells inflect harm through signaling, it doesn't take many such cells to act as a contributing cause of age-related disease and organ dysfunction.

The research community is nowadays fully invested in the concept that senescent cells are a meaningful cause of aging. This is a comparatively recent development, despite the fact that the evidence was sizable and evident for several decades. It took a great deal of hard work, advocacy, and philanthropy in order to bring about this change; the medical research and development communities had essentially relinquished their responsibilities in the matter of aging. Now, however, there is a great deal of funding for research groups interested in the biochemistry of senescent cells.

While most clinical development is focused on selective destruction of senescent cells as a way to reverse their contribution to the aging process, and this seems the best path forward, there is nonetheless a sizable faction in the research community whose members are more interested in modulating the bad behavior of senescent cells. This largely means interfering the generation or consequences of the SASP in some way. One of the consequences of SASP signaling is that nearby cells are encouraged to become senescent themselves. In today's open access paper, the authors report on their investigation of the mechanisms involved in this behavior.

Small Extracellular Vesicles Are Key Regulators of Non-cell Autonomous Intercellular Communication in Senescence via the Interferon Protein IFITM3

The establishment of cellular senescence is categorized by a stable cell-cycle arrest and the capacity to modify the microenvironment through a particular secretome called SASP (senescence-associated secretory phenotype). The activation of senescence is a response to different cellular stresses to prevent the propagation of damaged cells and has been shown to occur in vitro and in vivo. In fact, an enrichment in the number of senescent cells has been observed in vivo during both biological and pathological processes such as development, cancer, fibrosis, and wound healing.

The SASP controls its surroundings by reinforcing senescence in an autocrine (cell autonomous) and paracrine (non-cell autonomous) manner, by recruiting immune cells to eliminate senescent cells and by inducing a stem cell-like phenotype in damaged cells. The SASP provides the necessary balance to restore tissue homeostasis when it has been compromised. Paradoxically, the SASP can also contribute to the enhancement of tissue damage and the induction of inflammation and cancer proliferation. Overall, the mechanisms behind the pleiotropic activities of the SASP in different contexts are not well understood.

Most studies in vitro and in vivo have attributed the diverse functions of the SASP to individual protein components such as interleukin-6 (IL-6) or IL-8 to reinforce autocrine senescence or transforming growth factor β (TGF-β) as the main mediator of paracrine senescence or to a dynamic SASP with a switch between TGF-β and IL-6 as predominant individual components. However, it is still unclear how these diverse SASP components regulate senescence. In fact, inhibition of the SASP by blocking the mammalian target of rapamycin (mTOR) only partially prevents paracrine senescence, suggesting that alternative mechanisms may exist.

Exosomes are small extracellular vesicles (sEVs) (30-120 nm) of endocytic origin, whereas microvesicles are formed by the shedding of the plasma membrane. Exosomes and microvesicles are secreted by all cell types and found in most bodily fluids. Although some studies have found an increase in the number of EVs released during senescence, very little is known regarding the role that EVs play as SASP mediators in the senescent microenvironment.

Here, we show that both the soluble and sEV fractions of the SASP transmit paracrine senescence. The analysis of individual cells internalizing sEVs using a reporter system shows a positive correlation between the uptake of sEVs and paracrine senescence. sEV protein characterization by mass spectrometry (MS) followed by a functional small interfering RNA (siRNA) screen identify the interferon (IFN)-induced transmembrane protein 3 (IFITM3) within sEVs as partially responsible for transmitting senescence to normal cells. It is interesting that elderly human donors release more sEVs and that the sEVs found in plasma show higher protein levels of IFITM3 in 60% of the elderly donors. Although it may be tempting to speculate that IFITM3 within sEVs could be involved in aging, a larger cohort of young and elderly patients would be needed.

In conclusion, we show here that sEVs are responsible for mediating paracrine senescence and speculate that they could be involved in inducing bystander senescence during therapy-induced senescence or aging. In fact, when compared to soluble factors, sEVs have different biophysical and biochemical properties as they have a longer lifespan than do soluble factors and they are more resistant to protease degradation. The idea that blocking sEV secretion could be a potential therapeutic approach to alleviate senescence "spreading" during chemotherapy-induced senescence or in aging tissues presents itself as a very attractive tool for the future.

Telomere Dynamics with Age are Very Different Between Mammalian Species

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. They shorten with each cell division, a part of the mechanism that ensures somatic cells can only replicate a limited number of times. Telomerase acts to lengthen telomeres, and in humans telomerase is only active in stem cells. Thus our cells exist in a two-tier system, in which only tiny populations of privileged stem cells are permitted unrestricted replication, while the vast majority of somatic cells are limited. Matters are similar across all higher animals, and this state of affairs likely evolved because it keeps cancer to a low enough level, and pushed off far enough into late life, for allow for evolutionary success.

A lot of ink has been spilled on the topic of telomere length because, statistically across large populations, average telomere length and proportion of short telomeres tends to decrease with advancing age. Given that stem cell activity declines with age, this is most likely a reflection of a lower pace of creation of new somatic cells with long telomeres. The human data is complicated by the fact that telomere length is most commonly measured in immune cells from a blood sample, and is thus a very dynamic measure influenced by the day to day reactions of the immune system. In individuals, there isn't much anyone can do with measures of telomere length, given that it is so variable over time and between people of similar health and age: it is a terrible biomarker for any practical purpose.

Further, can we actually use anything that we learn about telomere dynamics in other species? It is well known that mouse telomere dynamics and telomerase expression are quite different from that of humans. This might make us suspect that positive results from telomerase gene therapies in mice, where life span is extended and health improved, without raising the risk of cancer, may not hold up in humans. There is no particular reason why increased cancer risk through putting damaged cells back to work will be balanced in the same way by improved tissue function and improved immune function, from species to species. The research and development community will find out in the years ahead by trying telomerase gene therapies in primates and then humans.

I feel that the open access paper here adds to doubts about the value that the research community can extract from a study of telomeres and telomerase in other mammalian species, though the researchers don't present it in that way. If various short and long lived mammals can have such a range of telomere dynamics, what are we supposed to make of the data resulting from animal studies of any therapeutic approach to targeting telomeres?

Telomeres and Longevity: A Cause or an Effect?

Since telomere dynamics were found to be better predictors of survival and mortality than chronological age in wild populations, many cross-sectional and longitudinal studies have been conducted on different organisms with variations in maximum life span investigating the relationship between chronologic age and telomere shortening. Yet, some studies have reported a lack of telomere shortening with age or even an increase in telomere length in organisms with exceptional longevity. Therefore, studying telomere dynamics in long-lived organisms is of particular importance since they may have developed mechanisms that actively postpone senescence and promote effective defenses against the deteriorating effects of aging processes.

The naked mole-rat (Hetercephallus glabers/NMR) and the blind mole-rat (Spalax ehrenbergi) are both considered excellent models for studying aging. They both exhibit extraordinary longevity with a maximum lifespan of approximately 30 years in NMRs (10 times longer than any other rodent of the same size) and 20 years in captivity for Spalax. They exhibit lifelong maintenance of superior anti-aging mechanisms leading to unchanged physiological functions and negligible senescence. Moreover, both of these mole-rats live in a presumably relatively stressful environment due to their subterranean lifestyle where they experience darkness, low oxygen and high carbon dioxide concentrations. Despite all these common features, NMRs and Spalax belong to different families; they are different in size and have different social lifestyles.

Whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence, and promote longevity is still an ongoing debate. In the current study, we aimed to investigate the relationship between telomere length and age in NMRs and Spalax. We tested blood telomeres in NMRs and three different tissues in Spalax and compared each one with a short-lived animal of their size.

While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

The Question of a Limit to Human Life Span

There has been much discussion in the aging research community these past few years on the topic of whether or not there is a limit to human life span, and how one might even go about defining such a thing. While life spans are in a slow upward trend due to general improvements in medical technology, can this trend continue without end, or will it run into a roadblock? In essence this is a debate over what can be extracted from poor data, and which data is in fact poor. Since there are few extremely old people, and since verifying age becomes ever harder the further back one has to go to search for records, the data for human mortality at advanced ages is very open to interpretation and reinterpretation, highly dependent on statistical methodologies used, and opinions on reliability of various sources of data.

In a more practical sense, this is all a storm in a teacup. Obviously there are mechanisms at work that ensure that even the statistical outliers don't make it much past 120. Autopsies carried out on supercentenarians revealed transthyretin amyloidosis, and consequent heart failure, as the dominant cause of death. It is reasonable to hypothesize that this form of age-related damage ensures the effective upper limit on human life span - in the sense that there is no hard limit, but if critical organ dysfunction ensures that mortality rates are 50% yearly or higher, then the odds catch up pretty quickly.

Equally obviously, all of this is absolutely dependent on the present state of medical technology. If transthyretin amyloid can be broken down, such as via the theraputic approach developed by Covalent Bioscience, then the result will be that everyone who periodically undergoes the treatment will live longer. The same goes for clearance of senescent cells, and all the rest of the SENS program of ways to repair the causes of aging. If medical technology addresses the damage of aging, then the length of life changes.

A related topic is the question of whether or not mortality rates stop increasing in very late life. Studies show that extremely old flies stop aging, in the sense that aging is defined as an increase in mortality rate per unit time. The flies have very high mortality rates, as is fitting for being in very poor shape, burdened by the damage of aging, but those very high rates appear to plateau. Over the past fifteen years, various analyses have suggested and then refuted that such a plateau exists in humans. Again we come back to the point that the data for very advanced ages isn't all that great, and so there tends to be a great deal of debate. At present, the balance of evidence and argument suggests that, for our species at least, mortality rates do keep increasing past the age of 110.

Are We Approaching a Biological Limit to Human Longevity?

Until recently human longevity records continued to grow in history, with no indication of approaching a hypothetical longevity limit. Also, earlier studies found that age-specific death rates cease to increase at advanced ages (mortality plateau) suggesting the absence of fixed limit to longevity too. In this study we re-examine both claims with more recent and reliable data on supercentenarians (persons aged 110 years and over).

We found that despite a dramatic historical increase in the number of supercentenarians, further growth of human longevity records in subsequent birth cohorts slowed down significantly and almost stopped for those born after 1879. We also found an exponential acceleration of age-specific death rates for persons older than 113 years in more recent data. Slowing down the historical progress in maximum reported age at death and accelerated growth of age-specific death rates after age 113 years in recent birth cohorts may indicate the need for more conservative estimates for future longevity records unless a scientific breakthrough in delaying aging would happen.

Many gerontologists are now more conservative regarding the future growth of longevity, citing results confirm that further growth of maximum lifespan for humans becomes an increasingly difficult task. Still there are reasons for cautious optimism here. Systematic analysis of human mortality throughout the 20th century revealed that, once a particular cause of death is accounted for, there is a proportional increase in both median age of death and maximum life span. So the authors of this study believe that application of aging-focused interventions could result in a continued increase not only in the median, but in maximal life span in humans as well.

Further research is needed to overcome obvious limitations of our study by addressing remaining concerns about data quality and representativeness, as well as increasing sample sizes. Still the data used in our study are the best available data so far, and their analysis suggests that there may be a provisional limit to human life in our current state of biomedical knowledge.

Inducing the Heat Shock Response as a Potential Treatment for Atherosclerosis

The heat shock response is one of a number of cellular maintenance processes that works to keep cells functional under circumstances of stress. As the name implies, heat is one of those stresses in this case, but the heat shock response is also triggered by other stresses as well. Further, the heat shock response has a role in resolving inflammation. Researchers here note that the heat shock response is suppressed in atherosclerosis, possibly as a result of the chronic inflammation induced by the presence of senescent cells, possibly due to other mechanisms, and that this might be an important factor in the progression of the condition. The study shows that upregulating the heat shock response via heat treatment produces benefits in atherosclerotic mice, and the authors suggest this might function via reductions in cholesterol levels and reductions in inflammation.

While acute inflammatory responses evolved to protect organisms against pathogens and to provide tissue repair under sterile injuries, they are rapidly resolved by several physiological feedback systems aimed at avoiding the perpetuation of inflammation. In this sense, the heat shock (HS) response, i.e., the anti-inflammatory program mainly centered in heat shock factor-1 (HSF1)-dependent expression of heat shock proteins (HSPs) and other anti-aggregative protein chaperones, powerfully resolves acute inflammation by shutting off nuclear factor κB (NF-κB) and other downstream pro-inflammatory signals.

Nevertheless, if injuring stimuli become chronic, HSF1 expression is severely blunted and cells stop producing cardioprotective HSPs (e.g., HSP27, HSP72), which are anti-inflammatory. This is the case of many (if not all) chronic degenerative diseases of inflammatory nature. In contrast, inducers of the HS response clearly reverse vascular lesions in atherosclerotic models. However, the development of atherosclerotic lesions is also associated with the blockade of the expression and activity of sirtuin-1 (SIRT1), which, in turn, underlies both HSF1 expression and transcribing activity. Therefore, in an atherosclerotic milieu, the physiological resolution of inflammation is critically jeopardized thus contributing to foam cell formation and vascular senescence observed in atherosclerosis.

These observations led us to hypothesize that disruption of the anti-inflammatory and anti-senescent HS response pathways could underlie the perpetuation of vascular inflammation in atherosclerosis, as observed in other chronic inflammatory diseases, and that in vivo heat treatment, the most powerful trigger of the HS response, should be effective in re-establishing SIRT1-HSF1-HSP axis in atherosclerotic mice.

Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal healthy counterparts, which was paralleled by increased expression of NF-κB-dependent VCAM1 adhesion molecule. Conversely, heat treatment completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of triacylglycerols, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose, and insulin resistance while rising HDL-cholesterol levels. Heat treatment also decreased body weight gain, visceral fat, cellular infiltration, and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance indices. Remarkably, heat-treated mice stopped dying after the third heat treatment session, suggesting a curative effect.

Becoming More Physically Active in Middle Age or Later in Life Improves Longevity

It is well recognized that physical activity and strength training correlate with improved life expectancy in later life. In animal studies, it can be shown that exercise causes increased healthy life spans. The study here reinforces that mountain of data. It is also interesting for adding to the evidence to show that the greatest benefits for increased activity occur in people who were sedentary. The dose response curve for exercise provides the greatest benefits when moving between no exercise and a sensible level of regular moderate exercise. Above that, there are still further benefits to be obtained, but gains in life expectancy taper off. To turn that around, being sedentary is very harmful to health over the long term. Try not to be sedentary.

Physical activity is associated with lower risks of all cause mortality, cardiovascular disease, and certain cancers. However, much of the epidemiology arises from observational studies assessing physical activity at a single point in time, and associations with subsequent mortality and chronic disease outcomes. As physical activity behaviours are complex and vary over the life course, assessing within-person trajectories of physical activity over time would better characterise the association between physical activity and mortality.

Participants in this study were 14,599 men and women (aged 40 to 79) from the European Prospective Investigation into Cancer and Nutrition. Physical activity energy expenditure (PAEE) was derived from questionnaires, and calibrated against combined movement and heart rate monitoring. Long term increases in PAEE were inversely associated with mortality, independent of baseline PAEE. For each 1 kJ/kg/day per year increase in PAEE (equivalent to a trajectory of being inactive at baseline and gradually, over five years, meeting the World Health Organization minimum physical activity guidelines of 150 minutes/week of moderate-intensity physical activity), hazard ratios were: 0.76 for all cause mortality, 0.71 for cardiovascular disease mortality, and 0.89 for cancer mortality, adjusted for baseline PAEE, and established risk factors.

In conclusion, we showed that middle aged and older adults, including those with cardiovascular disease and cancer, stand to gain substantial longevity benefits by becoming more physically active, irrespective of past physical activity levels and established risk factors - including overall diet quality, body mass index, blood pressure, triglycerides, and cholesterol. Maintaining or increasing physical activity levels from a baseline equivalent to meeting the minimum public health recommendations has the greatest population health impact, with these trajectories being responsible for preventing nearly one in two deaths associated with physical inactivity. In addition to shifting the population towards meeting the minimum physical activity recommendations, public health efforts should also focus on the maintenance of physical activity levels, specifically preventing declines over mid to late life.

A Potential Approach to Reducing TDP-43 Proteopathy in the Aging Brain

Most neurodegenerative conditions are associated with the build up of damaging protein aggregates that degrade cell function or kill cells in the brain. The amyloid-β and tau of Alzheimer's disease and α-synuclein of Parkinson's disease are well known, but TDP-43 is not as well recognized beyond the that part of the research community focused on it. Here, scientists outline a potential approach to small molecule drugs that might reduce the tendency of TDP-43 to form aggregates. That is a first step on the road to therapies capable of slowing the progression of conditions such as amyotrophic lateral sclerosis (ALS) that are associated with TDP-43 pathology, but it is still a way removed from a full solution to the problem.

Researchers discovered that prolonged cellular stress, such as exposure to toxins, triggers TDP-43 clumping in the cytoplasm of human motor neurons grown in a laboratory dish. Even after the stress is relieved, TDP-43 clumping persists in ALS motor neurons, but not in healthy neurons. The team then screened and identified chemical compounds (potential precursors to therapeutic drugs) that prevent this stress-induced, persistent TDP-43 accumulation. These compounds also increased the survival time of neurons with TDP-43 proteins containing an ALS-associated mutation.

The researchers generated motor neurons from induced pluripotent stem cells (iPSCs) that had been converted from human skin cells. To mimic cellular aspects of ALS, they exposed these laboratory motor neurons to toxins such as puromycin, which stressed the cells and led to TDP-43 clumps. Normally, TDP-43 proteins help process molecules called messenger RNA, which serve as the genetic blueprints for making proteins. But when they clump outside the nucleus, TDP-43 proteins can't perform their normal duty, and that can have a profound effect on many cellular functions.

The researchers tested thousands of chemical compounds for their effects on RNA-protein aggregation. They were surprised to find compounds that not only reduced the overall amount of clumping by up to 75 percent, but also varied clump size and number per cell. Some of the compounds tested were molecules with extended planar aromatic moieties - arms that allow them to insert themselves in nucleic acids, such as DNA and RNA. TDP-43 must bind RNA in order to join ALS-associated clumps. Thus it makes sense that a compound that interacts with RNA would prevent TDP-43 from clumping.

Vascular Calcification and Inflammation in Chronic Kidney Disease

Kidney degeneration goes hand in hand with cardiovascular disease and neurodegeneration in aging; kidney function is one of the better examples of the way in which deterioration in one organ system causes issues in many others. Nothing in our biology exists in isolation. Researchers here discuss the present state of knowledge regarding vascular calcification in the context of age-related chronic kidney disease. There is a particular focus on the role of chronic inflammation, given the way in which it disrupts all sorts of essential tissue maintenance processes. The accumulation of senescent cells is one of the more important contributions to chronic inflammation, and there is evidence for these cells to be influential in the calcification of blood vessels, and corresponding loss of flexibility.

Low kidney function is linked to poor health outcomes, with clinical manifestations in a wide variety of other organ systems, and is associated to a much higher risk of cardiovascular disease. The risk of cardiovascular disease exponentially increases as kidney function declines, being the major contributor to the high incidence of cardiovascular complications and death in this population. This is partially due to vascular calcification (VC) and accelerated atherosclerosis, as a result of the mineral and bone disorder that often accompanies low kidney function and complicates chronic kidney disease (CKD).

In addition to the complexity of mechanisms involved in VC initiation and progression, it is currently accepted that it cannot be regarded as an isolated pathological process, with several studies providing compelling evidence that VC is highly interconnected with inflammation. In fact, it has been suggested that pathological calcification and chronic inflammation are involved in a positive feedback loop driving disease progression.

Early stages of CKD are already associated with up-regulation of proinflammatory and pro-osteogenic molecules in the vascular wall and calcification of the aortic media. In fact, several lines of evidence indicate that inflammation triggers and precedes osteogenic conversion of vascular smooth muscle cells (VSMCs) and the release of calcifying extracellular vesicles (EVs), promoting the calcification process. It is likely that the effect of inflammation on VC occurs at multiple and interconnected levels. It has been proposed that inflammation might regulate VC, at least in part, through activation of an endoplasmic reticulum stress pathway, which in turn may increase inorganic phosphate uptake, leading to increased VSMCs osteogenic differentiation and increased mineral deposition.

Remarkably, this inflammation/vascular calcification crosstalk described in CKD pathology shares many similarities with the aging process in the general population, including the inflammaging and VSMCs senescence. Inflammaging is a recently adopted term do define a state of low grade chronic inflammatory condition, associated with a significant risk factor for morbidity and mortality in the elderly. Cellular senescence, in general, has been proposed as a potential mechanism of aging and age-related diseases, which can be triggered by a number of mechanisms and leading to an altered secretome, termed the senescence-associated secretory phenotype (SASP). In the particular case of VSMCs, senescence has been shown to enhance vascular calcification and inflammation, with pro-calcific and pro-inflammatory SASPs.

VSMCs senescence and associated SASP have been suggested to contribute to chronic vascular inflammation and calcification, loss of arterial function, and the development of age-related diseases. Thus, it has been suggested that altered vascular health under CKD settings might represent an example of premature aging. In this context, it could be conceivable that new knowledge about molecular mechanisms, such as the crosstalk between VC and inflammation, in CKD, might shed new light on the aging process, and vice versa.

OncoSenX Raises 3 Million to Adapt the Oisin Biotechnologies Platform to Cancer

Oisin Biotechnologies uses a form of programmable suicide gene therapy to target senescent cells for destruction. The therapy can be triggered by expression of specific genes inside a cell, and so beyond senescent cells there is a long, long list of possibly harmful cell populations in aging and disease that it would be beneficial to remove. The obvious first choice is cancerous cells with a mutation in one of the common cancer suppressor genes, such that the gene is expressed but not helping. Thus Oisin Biotechnologies spun out OncoSenX last year. The company is moving forward towards trials, and recently raised a seed round to fund the work of the next few years.

OncoSenX, Inc., a late preclinical-stage company developing therapeutics to kill cancer cells based on their genetics, today announced it has raised 3 million in pre-seed funding to advance its pipeline. "These funds will allow us to accelerate the preclinical research necessary for us to begin phase 1 clinical development. We believe our non-viral gene therapy for solid tumors represents the first in a new class of cancer therapeutics. The OncoSenX team is diligently working to bring this new approach into the clinic for the benefit of a global oncology community clearly in need of new options."

OncoSenX is developing a highly selective tumor-killing platform with two main components: a proprietary lipid nanoparticle (LNP) for cellular delivery and a highly selective DNA payload. The LNP is designed to deliver its non-integrating DNA payload to solid tumors, while an engineered promoter drives expression of a potent, inducible death protein only in the target cell population. The goal is to precisely target cell populations based on their genetic activity without harming nearby cells. The platform can be effectively programmed to implement logic gates (IF/OR/AND) to provide selectivity to any target cell based on its genetics.

"Our preclinical studies suggest the OncoSenX approach has the potential to precisely kill cancer cells based on the mutations they harbor. If substantiated in the clinic, the platform could deliver reduced toxicity and improved tolerability over conventional chemotherapy, with the potential for superior targeting over biologics or even CAR-T therapy."

Applying Bacterial Homing Strategies to Target Stem Cells to Heart Tissue

Most classes of therapy benefit from some form of targeting or selectivity, helping to direct them to the tissue of interest, and away from other places where they might cause side-effects. Cells are difficult to work with, but they are also much more capable of selective targeting, since they can migrate. Many types of cell reliably find their way from one part of the body to another in the course of their functions, but where no suitable mechanism exists in human biochemistry, it is sometimes possible to look elsewhere. Here, researchers adapt a bacterial targeting system and apply it to the stem cells that might be used in regenerative therapies for damaged heart tissue.

To date, trials using stem cells, which are taken and grown from the patient or donor and injected into the patient's heart to regenerate damaged tissue, have produced promising results. However, while these next generation cell therapies are on the horizon, significant challenges associated with the distribution of the stem cells have remained. High blood flow in the heart combined with various 'tissue sinks', that circulating cells come into contact with, means the majority of the stem cells end up in the lungs and spleen.

"We know that some bacterial cells contain properties that enable them to detect and 'home' to diseased tissue. For example, the oral bacterial found in our mouths can occasionally cause strep throat. If it enters the blood stream it can 'home' to damaged tissue in the heart causing infective endocarditis. Our aim was to replicate the homing ability of bacteria cells and apply it to stem cells." The team developed the technology by looking at how bacterial cells use a protein called an adhesin to 'home' to heart tissue. Using this theory, the researchers were able to produce an artificial cell membrane binding version of the adhesin that could be 'painted' on the outside of the stem cells. In an animal model, the team were able to demonstrate that this new cell modification technique worked by directing stem cells to the heart in a mouse.

"Our findings demonstrate that the cardiac homing properties of infectious bacteria can be transferred to human stem cells. Significantly, we show in a mouse model that the designer adhesin protein spontaneously inserts into the plasma membrane of the stem cells with no cytotoxity, and then directs the modified cells to the heart after transplant. To our knowledge, this is the first time that the targeting properties of infectious bacteria have been transferred to mammalian cells."

Reviewing Resistance Training as an Intervention to Reduce Chronic Disease Risk

A sizable body of evidence points to the ability of resistance training undertaken in later life to reduce the risk of suffering age-related disease, and to improve the prognosis for existing diseases. In a glass half empty sort of a viewpoint, we might take this to mean that next to nobody puts in the effort necessary to maintain the body in an optimal state of health. A surprisingly sizable fraction of the declines in strength and fitness observed in the wealthier parts of the world are actually self-inflicted, not an inevitable consequence of aging. This is particularly apparent in comparisons with hunter-gatherer populations, where exercise and fitness persist into late middle age, and the declines that are inevitable are lessened.

The progressive decline of skeletal muscle mass and strength with aging is collectively referred to as sarcopenia, and is prognostic for mobility disability and chronic disease risk. Regular physical activity (defined here as any bodily movement produced by the contraction of skeletal muscle that increases energy expenditure) and exercise (physical activity that is planned, structured, and repetitive) are cornerstones in the primary prevention of chronic diseases and also for mitigating risk of mobility disability in older persons.

Resistance exercise (RE) and aerobic exercise (AE) are modalities of exercise that are traditionally conceptualized as existing on opposite ends of an exercise continuum in terms of the phenotypes they lead to. A common misconception is that RE training (RET) and AE training (AET) also result in separate health benefits, but we propose this is an artifact of the greater volume of data that currently exists for AET as opposed to RET. Currently, most physical activity guidelines advise, as their primary message, that older adults should perform at least 150 min of moderate-to-vigorous or 75 min of vigorous AET weekly for the reduction of chronic disease risk and maintenance of functional abilities. However, there is an emerging body of evidence to suggest that RET can be as effective as AET in reducing chronic disease risk and is particularly potent for maintaining mobility in older adults.

It may be that RET is more effective than AET in some regards; the converse is likely also true. We posit that the perceived divergent exercise mode-dependent health benefits of AET and RET are likely small in most cases. In this short review, our aim is to examine evidence of associations between the performance of RET and chronic health disease risk (mobility disability, type 2 diabetes, cardiovascular disease, cancer). We also postulate on how RET may be influencing chronic disease risk and how it is a critical component for healthy aging. Accumulating evidence points to RET as a potent and robust preventive strategy against a number of chronic diseases traditionally associated with the performance of AET, but evidence favors RET as a potent countermeasure against declines in mobility. On the basis of this review we propose that the promotion of RET should assume a more prominent position in exercise guidelines particularly for older persons.

Quiescence of Stem Cells in Aging as a Double Edged Sword

Stem cells spend much of their time in the quiescent stage of the cell cycle, resting without replication in a state of lower metabolic activity. The open access review paper here is an interesting look at why quiescence is both helpful and problematic in the context of the contribution of stem cell dysfunction to aging and age-related disease. The purpose of stem cells is to support the surrounding tissue by providing a supply of daughter somatic cells to replace losses and repair damage. Stem cell populations decline in this activity with aging, due to a mix of cellular damage, a fall in numbers, and increasing quiescence. To the degree that the latter of these issues is dominant, it should be possible to find ways to push stem cells back into greater activity. Indeed, many present approaches to regenerative medicine aim at this goal.

The quiescence stage of stem cells has beneficial and adverse effects on stem cell aging. Stem cell quiescence delays stem cell aging by reducing DNA replication, metabolic activity, gene transcription, and mRNA translation, since all of these activities are accompanied by induction of molecular damage. Stem cell quiescence comes at the cost of impaired expression of repair factors in quiescence and increased vulnerability in response to stem cell activation requiring the concerted and faithful activation of multiple molecular circuits that control biosynthetic processes, repair, and metabolic activity.

Aging-associated increases in stem cell-intrinsic accumulation of molecular damage as well as stem cell-extrinsic alterations (e.g., chronic inflammation, niche cell defects) contribute to the deregulation of quiescence maintenance and increasing vulnerability during exit from quiescence. Epigenetic alterations occur during aging in quiescent and activated stem cells and lead to aberrant expression of developmental genes resulting in alterations of quiescence maintenance, self-renewal, and differentiation.

In conclusion, quiescence protects stem cells against molecular damage but comes at the cost of aging-associated failure in the correct regulation of quiescence maintenance and exit. Activation of quiescent stem cells - an essential process for organ homeostasis/regeneration - requires concerted and faithful regulation of multiple molecular circuits that control biosynthetic processes, repair mechanisms, and metabolic activity. Thus, while protecting stem cell maintenance, quiescence comes at the cost of vulnerability during the process of stem cell activation.

Aging is Accompanied by a Systemic Downregulation of Long Transcripts

Cells are state machines whose behavior is regulated by the pace of production of specific proteins from their genetic blueprints, a process called gene expression. Feedback loops exist between cell activities, the surrounding environment, signals coming and going, and gene expression. Researchers here examine the first part of the gene expression process, in which RNA transcript molecules are generated, and find that there is an association between the size of these molecules and changes in abundance with age. This suggests that some fundamental part of the machinery of transcription is degraded with age, likely producing dysfunction in a range of cellular behavior. The researchers point the finger at SFPQ, though it might be a little early in the investigation of this effect to say anything with confidence about why it happens and what the root causes might be.

The transcriptome responds rapidly, selectively, strongly, and reproducibly to a wide variety of molecular and physiological insults experienced by an organism. While the transcripts of thousands of genes have been reported to change with age, the magnitude by which most transcripts change is small in comparison with classical examples of gene regulation and there is little consensus among different studies. We hence hypothesize that aging is associated with a hitherto uncharacterized process that affects the transcriptome in a systemic manner. We predict that such a process could integrate heterogenous, and molecularly distinctive, environmental insults to promote phenotypic manifestations of aging.

We use an unsupervised machine learning approach to identify the sources of age-dependent changes in the transcriptome. To this end, we measure and survey the transcriptome of 17 mouse organs from 6 biological replicates at 5 different ages from 4 to 24 months raised under standardized conditions. To identify whether there are universal architectural or regulatory features informative on age-dependent changes, we systematically analyze feature importance across models. The most informative feature to those models is the median length of mature transcript molecules, which is closely followed by the number of transcription factors, the length of the gene, and the median length of the coding sequence. We conclude that during aging, transcript length is the most informative feature.

We report a hitherto unknown phenomenon, a systemic age-dependent length-driven transcriptome imbalance that for older organisms disrupts the homeostatic balance between short and long transcript molecules for mice, rats, killifish, and humans. We also demonstrate that in a mouse model of healthy aging, length-driven transcriptome imbalance correlates with changes in expression of splicing factor proline and glutamine rich (Sfpq), which regulates transcriptional elongation according to gene length. Furthermore, we demonstrate that length-driven transcriptome imbalance can be triggered by environmental hazards and pathogens. Our findings reinforce the picture of aging as a systemic homeostasis breakdown and suggest a promising explanation for why diverse insults affect multiple age-dependent phenotypes in a similar manner.

Killer T Cells Invade the Aging Brain and Disrupt Generation of New Neurons

The blood-brain barrier is a lining of specialized cells wrapping blood vessels, in place to keep the central nervous system isolated from the rest of the body. Unfortunately, and like all aspects of our biology, the blood-brain barrier becomes dysfunctional with age, and this allows cells from other parts of the body to infiltrate the brain. As the research results here demonstrate, this is particularly problematic in the case of immune cells that should not normally be present in the brain. By generating inflammatory signals, these invading cells can disrupt vital activities of neurons or the stem cells responsible for generating new neurons.

Many a spot in a young mammal's brain is bursting with brand new neurons. But for the most part, those neurons have to last a lifetime. Older mammals' brains retain only a couple of neurogenic niches, consisting of several cell types whose mix is critical for supporting neural stem cells that can both differentiate into neurons and generate more of themselves. New neurons spawned in these niches are considered essential to forming new memories and to learning, as well as to odor discrimination.

In order to learn more about the composition of the neurogenic niche, researchers catalogued, one cell at a time, the activation levels of the genes in each of nearly 15,000 cells extracted from the subventricular zone (a neurogenic niche found in mice and human brains) of healthy 3-month-old mice and healthy 28- or 29-month-old mice. When the researchers compared their observations in the brains of young mice (equivalent in human years to young adults) with what they saw in the brains of old mice (equivalent to people in their 80s), they identified a couple of cell types in the older mice not typically expected to be there - and barely present in the young mice. In particular, they found immune cells known as killer T cells lurking in the older mice's subventricular zone.

The healthy brain is by no means devoid of immune cells. In fact, it boasts its own unique version of them, called microglia. But a much greater variety of immune cells abounding in the blood, spleen, gut and elsewhere in the body are ordinarily denied entry to the brain, as the blood vessels pervading the brain have tightly sealed walls. The resulting so-called blood-brain barrier renders a healthy brain safe from the intrusion of potentially harmful immune cells on an inflammatory tear as the result of a systemic illness or injury.

Further experiments demonstrated several aspects of the killer T cells' not-so-mellow interaction with neural stem cells. For one thing, tests in cell cultures and in living animals indicated that killer T cells isolated from old mice's subventricular zone were far more disposed than those from the blood of the same mice to pump out an inflammation-promoting substance that stopped neural stem cells from generating new nerve cells. Second, killer T cells were seen nestled next to neural stem cells in the subventricular zones of old mice and in tissue taken from the corresponding neurogenic niche in autopsied brains of old humans; where this was the case, the neural stem cells were less geared up to proliferate.


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