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- Calorie Restriction and Calorie Restriction Mimetics Dampen Inflammation
- Macrophage Polarization in Aging is Complicated and Poorly Understood
- The Concept of Successful Aging is Harmful to Research and Development
- Cellular Senescence in the Bone Marrow as a Contributing Cause of Osteoporosis
- Loss of Lung Function Correlates with Epigenetic Age Acceleration
- Astrocyte Senescence Causes Death of Neurons in Cell Culture
- Premature Menopause Correlates with Greater Later Incidence of Chronic Disease
- More on the SASP Atlas, a Basis for Biomarkers of Aging
- A Conservative View on Lifestyle versus Pharmacological Interventions for Aging
- Combination Gene Therapy for α-Klotho and TGFβR2 Improves Osteoarthritis in Mice
- Senolytic Treatment Fails to Reverse Uterine Fibrosis in Mice
- Dicer1 Gene Therapy as a Treatment for Age-Related Macular Degeneration
- The Role of Lipids in Metastasis Offers Therapeutic Targets that May Work for Many Cancers
- A Guide Implant Allows Regrowth of Inches of Lost Nerve Tissue
- Loss of Volume in the Cerebellum Correlates with Memory Decline with Age
Calorie Restriction and Calorie Restriction Mimetics Dampen Inflammation
Chronic inflammation is an important aspect of aging, a process that stems from low-level biochemical damage and cellular dysfunction, and that then contributes to the progression of age-related disease and tissue dysfunction. Chronic inflammation sustained over years accelerates all of the common fatal age-related conditions: it disrupts tissue maintenance, and leads to fibrosis, immune dysfunction, and many more issues. The chronic inflammation of aging is important enough that beneficial therapies have been built on the basis of suppressing inflammation directly, without addressing its causes. Treatments that actually address the causes should be very much better at the end of the day, of course.
Interventions that have been demonstrated to slow aging in laboratory species tend to act to suppress the age-related increase in inflammation - they would have to, in order to achieve the outcome of a longer, healthier life in these animals. Calorie restriction is the best studied of these interventions, and a wide range of calorie restriction mimetic drugs have arisen from this field of research, compounds that mimic a fraction of the overall metabolic response to a lower intake of calories. Today's open access paper reviews what is known of the way in which mechanisms of the calorie restriction response act to reduce chronic inflammation and its impact on age-related disease.
A sizable fraction of the inflammation of aging arises from the presence of senescent cells. These cells grow in number with age, and their signaling produces a range of detrimental effects on surrounding tissue, of which chronic inflammation is just one - though, as noted here, an important one. Calorie restriction adopted in later life doesn't impact the burden of cellular senescence to anywhere near as great a degree as the use of senolytic drugs can achieve by selectively destroying senescent cells. That point is worth keeping in mind while looking over the paper noted here.
Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria
Under certain circumstances such as aging, there is a failure in the resolution mechanisms leading to the chronic activation of immune cells and persistent inflammation. This state of low-grade but chronic inflammation is known as inflammaging, and is characterized by increased levels of pro-inflammatory cytokines in the circulation. Notably, inflammaging is considered a risk factor for many age-related diseases. Even in certain tissues like the brain, that possesses a privilege protection against inflammation, certain signs of inflammation appear gradually with age, and this neuroinflammation can anticipate the appearance of some neurodegenerative diseases. In addition, the integrity of the intestinal barrier is compromised due to inflammatory stress during aging and contributes to the development of several diseases. Finding drugs that protect against inflammaging, the disruption of the intestinal barrier, and neuroinflammation should be a priority for geroscience in the next years.
Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. It is well known that an intense crosstalk exists between mitochondria and autophagosomes, and the activity or stress status of either one of these organelles may affect the other. A mitochondrial or autophagy decline compromises cellular homeostasis and induces inflammation. Furthermore, mitochondrial function and autophagy are key pathways controlling the activation of both the innate and the adaptive immune system. In the last decade, it has become evident that mitochondria are essential organelles that direct the fate of immune cells, giving rise to a new scientific discipline that is called immunometabolism. Moreover, the outcome of the inflammatory response can be controlled by modulating the metabolism of immune cells.
Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseases.
Macrophage Polarization in Aging is Complicated and Poorly Understood
Macrophages are a type of innate immune cell, and like all immune cells are involved in a great many processes in the body, ranging from tissue regeneration to clearing out molecular waste and debris to destruction of pathogens. Macrophages, and the similar microglia of the central nervous system, adopt different phenotypes, known as polarizations, depending on environment and the task at hand. The M1 polarization is pro-inflammatory and focused on ingestion of pathogens and debris, while the M2 polarization is anti-inflammatory and focused on regeneration. These are broad buckets and as such not truly representative of the real complexity of types and behaviors in these cell populations, but they are helpful enough for researchers to consider therapies based on forcing macrophages to preferentially adopt one polarization over another.
Earlier work on macrophage polarizations in aging suggested that issues arise with a growth in M1 populations and reduction in M2 populations, mirroring the rising chronic inflammation of aging. Matters are more complicated and tissue specific than that, however. To pick one illustrative example, today's open access commentary looks at what is known of polarization in the aging of muscle tissue, where the opposite trend is observed. The collective activities of cells, like cell metabolism itself, is a ferociously complicated domain and varies widely from tissue type to tissue type within the body. How these aspects of our biology change with age is yet another layer of complexity atop that, and little of it is completely mapped and understood at the detail level. Simple points of intervention, or global changes that can be made safely, are few and far between.
Macrophages in skeletal muscle aging
Macrophage function is largely mediated by a unique process of polarization. Depending on local environmental cues, macrophages polarize to pro-inflammatory M1 or anti-inflammatory M2 subtypes. In skeletal muscle, polarized macrophages regulate injury repair or infection resolution. Upon injury, infiltrated monocytes polarize to M1 and secrete proinflammatory cytokines to facilitate the elimination of pathogens and the cleanup of tissue debris. Subsequently, M2 macrophages that are converted from M1 and recruited from surrounding muscles jointly suppress inflammation and promote growth factors and collagen synthesis that contribute to injury repair. Accordingly, the blocking of the M1 to M2 transition resulted in defective repair, and the depletion of macrophages severely compromised muscle repair.
Contrary to muscle repair, the role of macrophage involvement in skeletal muscle aging is poorly understood. To gain insight into the function of macrophages in skeletal muscle aging, we analyzed their polarization status in aging human skeletal muscle. Considering that skeletal muscle aging inevitably occurs even in individuals devoid of obvious injury or infection, we studied resident macrophages from healthy older individuals in order to focus on normal/natural aging. We found that most macrophages in human skeletal muscle were M2, and the number increased with age. In contrast, M1 macrophages were much fewer in number, and decreased with age.
We further observed that macrophages closely co-localize with adipocytes in intermuscular adipose tissue (IMAT), but not satellite cells (muscle stem cells). This co-localization suggested possible mechanisms for the M2 increase and the actions of increased M2 in aging skeletal muscle. Adipocytes have been shown to secrete M2-promoting Th2 cytokines and adiponectin, and M2 was indeed the major macrophage population in adipose tissues in lean but not obese mice. We infer that adipocytes in IMAT contribute to the extensive M2 polarization in normal skeletal muscle, and that increased IMAT in aging skeletal muscle in non-obese, healthy people may be responsible for the M2 increase.
In keeping with the evidence that M2 macrophages are capable of regulating collagen synthesis and adipogenesis, we observed that collagen mRNA levels were dramatically reduced in aged mouse skeletal muscle, but collagen protein levels were comparable between aged and young muscle. We inferred from this observation that increased M2 macrophages may contribute to the stable collagen protein level in muscle. Consistent with this notion, increased M2 macrophages in aged skeletal muscle were shown to promote muscle fibrosis in mice.
Regarding adipogenesis, a recent study showed that M2 macrophages suppress adipocyte progenitor cell proliferation in mouse adipose tissue, and that the depletion of M2 macrophages enhanced the generation of small adipocytes and improved insulin sensitivity. In skeletal muscle, it was shown that M2 macrophages elevate adipogenesis by fibro-adipogenic progenitors (FAPs)/ncb2015">fibro-adipogenic progenitors (FAPs). Thus, increased M2 macrophages may contribute to fibrosis and fat infiltration, the two major features of skeletal muscle aging, although their exact function remains elusive.
The Concept of Successful Aging is Harmful to Research and Development
As illustrated in today's research commentary, all too many researchers continue to view aging as something distinct from age-related disease, and this inevitably leads to a poor approach to research and development. In this case, a rejection of the idea that rejuvenation is possible in principle at the present time. If one believes that aging and age-related disease are distinct, then one can also think that it is possible to age successfully, or age healthily. That we should split out the concepts of aging and disease, and only treat disease. This is all abject nonsense. There is no such thing as healthy aging or successful aging. There are processes of aging that can clearly be reversed, either actually or in principle. Too many people in positions of influence are producing irrational strategies for medical research under the belief that healthy aging is a viable goal.
Aging is by definition the accumulation of damage and dysfunction that raises mortality risk over time; it is a process of harm and loss. A "healthy" 80-year-old is in no way healthy by any objective measure. Can he sprint the way he used to? No. Is his hearing and eyesight the match of a youngster? No. Are his arteries damaged and distorted? Yes. Does he have a mortality risk that would raise eyebrows in a 20-year-old? Also yes. This is not health. This is a considerable progression towards the polar opposite of health.
To call any particular outcome of the damage and dysfunction at the roots of aging a disease is to draw an arbitrary line in the sand and say that some dysfunction is healthy, and won't be treated, while a little more dysfunction than that is unhealthy, and a disease that should be treated. Sadly this is exactly how medical science has progressed for all too long, even as the scientific understanding of aging needed for a better approach was assembled over the past century or more. The outcomes on either side of that arbitrary line in the sand (yes, you have clinical arthritis and will be treated, versus no, you have signs of progression towards clinical arthritis and come back later) all result from the same processes of damage taking place under the hood. This damage grows with time and leads inexorably to organ failure and death. Thus we should develop rejuvenation therapies to repair that damage, ideally long before it rises to the level of causing pathology. History teaches us that any other path is doomed to failure at worst and marginal, accidental gains at best.
Are We Ill Because We Age?
In the optic of geroscience, if aging becomes a treatable disease/process, it will be the duty of medical doctors to treat it. However, not everything which seems to be aging is aging. Over the history of gerontology and geriatrics, many processes previously thought to be part of aging are now considered not to be age-related, but an overlaying pathology. One of the best examples is anemia, which for decades was considered as a solid attribute of aging but now is considered related to various pathologies and not to aging itself. So, an older individual who does not have relevant underlying pathomechanisms would not have anemia even at 100 years of age or more. The same applies to hypertension, to sarcopenia, to kidney failure, and to cognitive impairment.
So again, what distinguishes aging from a disease conceptually? First, the extent of aging is systemic and complex while that of a disease is mostly limited. Aging is an inevitable, universal process (concerning all humans living long enough) while most diseases are associated with individuals' susceptibilities/vulnerabilities, and most of them, even chronic, are preventable. The most important cause of aging is time, while diseases usually have specific known causes. In other words, aging is irreversible and progressive while diseases are reversible and discontinuous. Finally, and most importantly, aging may be modulable but not treatable, while diseases are ultimately treatable even if we do not know presently how, which is only a question of progress of science. So many essential differences clearly speak against the notion that aging is "just another" disease.
we should ask how we would know if an anti-aging therapy really could slow aging. The problem is that most of our definitions are circular or impractical. At the most macro level, we might ask whether it extends lifespan or life expectancy. We might ask if we reduce the incidence or burden of age-related diseases (ARDs) with anti-aging interventions. However, it is possible we could do this by counteracting negative aspects of modern lifestyle (e.g., obesity), without affecting aging per se, and conversely that we might find interventions that slow aspects of aging without having much impact on ARDs. Lastly, we might ask whether anti-aging interventions have impacts on metrics of biological aging. If these metrics are specific metrics of the processes being treated, the reasoning becomes circular. For example, we could not prove that senolytics affect aging simply because they reduce the number of senescent cells. Higher level indicators of biological age, such as homeostatic dysregulation indices or the epigenetic clock, are slightly more promising metrics. However, even here there is a problem: these various indices are only poorly correlated with each other and are themselves based on various theories about what aging is. For example, if senolytics lower (rewind) the epigenetic clock, is this simply because the epigenetic profiles of senescent cells are different, and we have removed these cells from the mix? Or was there really an impact on aging in the remaining cells?
At this stage of our knowledge there is no place in medicine for anti-aging medicine understood as treating symptoms of aging when aging has already happened. However, there might be a place for interventions/modulations that would delay the occurrence of aging, when applied early in life, before any time-dependent processes had accumulated and aging symptoms show up. Scientists should recognize at this stage that we know a lot but not enough yet to translate the scientific discoveries in the field of gerontology to interventions into the older subjects. However, a new approach is needed and should be oriented at a systemic conceptualization of the aging process and not at the fragmentation of its different components.
Thus, better assessment of the biological aging against the chronological aging holds promises to be able (e.g., by significant biomarkers) to assess the physiological aging processes in their complexity and act on them specifically and jointly. The concept that aging does not always lead to ARD, but that the same processes may lead to either ARD or successful aging in older persons depending on the homeodynamics, will also help to individualize the interventions. Furthermore, the recognition that not everything occurring in aging is detrimental will help to design purposeful interventions to reinforce what is necessary and combat what IS detrimental. Finally, the recognition of aging as a lifelong process and that chronic diseases start early in life would help to design interventions very early in life having consequences on ARD. So, we should move from the aging as a disease concept to the aging as an adaptation, which may result in ARD or successful functional healthspan.
Cellular Senescence in the Bone Marrow as a Contributing Cause of Osteoporosis
Cellular senescence contributes meaningfully to near all age-related conditions, judging by the research of the past few years. In only a very few cases has clearance of senescent cells failed to perform well as a basis for therapy. In just the past year, papers have been published on the role of senescent cells in twenty or more very different age-related conditions. In many cases, the researchers demonstrated that clearance of a sizable fraction of the senescent cells present in tissues, using one of the available senolytic mouse models or small molecule therapies, reversed the progression of the age-related condition under study. When it comes to the diseases of aging, senolytic therapies are about as close to a panacea as it is possible to be, at least in animal studies.
Cells become senescent constantly, largely somatic cells reaching the Hayflick limit on replication. Cells also become senescent in reaction to DNA damage, environmental toxicity, tissue injury, and the signaling of senescent neighbors, however. Senescence is useful in the short term, assisting regeneration and suppressing cancer risk. But not all senescent cells self-destruct or are removed by the immune system, and the processes of clearance appear to slow down and become less efficient with age. The numbers of lingering senescent cells grow throughout the body, and the inflammatory signaling produced by these cells, useful in the short-term, becomes very harmful when sustained over months and years.
Today I'll point your attention to an open access review paper that discusses cellular senescence as a contributing cause of osteoporosis. It isn't the only contributing cause, but it appears sufficient in and of itself to cause the loss of bone mass and strength. Osteoporosis is, at the high level, an imbalance between the number and activity of cells building bone (osteoblasts) and the number and activity of cells breaking down bone (osteoclasts). Both osteoblasts and osteoclasts are continually active, and bone tissue is constantly remodeled. In youth, these processes of creation and destruction are in balance. The inflammatory signaling of senescent cells helps to disrupt that balance, tipping it in favor of osteoclast activity.
Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells
Senile osteoporosis is an age dependent bone disorder occurring both in men and women, which has become a worldwide health concern. The functional change of bone marrow stromal cells (BMSCs) has been demonstrated to contribute to senile osteoporosis, showing as BMSCs differentiate into fewer osteoblasts, but more adipocytes, and BMSCs become senescent. Besides the critical involvement of BMSCs in senile osteoporosis, BMSCs are also a favorite cell source for cell therapy and have been applied for osteoporosis treatment. Therefore, uncovering the underlying mechanisms of function changes of BMSCs during senile osteoporosis is important not only for better understanding the involvement of BMSCs in senile osteoporosis, but also for manipulating them for clinical applications.
Recent findings demonstrate that numerous transcriptional factors, signaling pathways, epigenetic regulations and other factors play key roles in regulating the differentiation and senescence of BMSCs, the alteration of which contributes to senile osteoporosis. Runx2 and PPARγ are two key transcription factors that are responsible for osteogenic differentiation and adipogenic differentiation of BMSCs, respectively. Decreased Runx2 expression and increased PPARγ results in senile osteoporosis. NRF2 and FOXP1 are two transcription factors related to the senescence of BMSCs by regulating antioxidant responsive genes. They are decreased with age, thus, leads to BMSCs senescence and bone loss. BMP signaling, Wnt signaling, and Notch signaling pathways all show dual roles in regulating osteogenic and adipogenic differentiation of BMSCs. They function either by targeting the downstream transcription factors, such as Runx2, PPARγ, or by cross-talking with each other.
Recently, p53/p21 and p16/Rb signaling pathways have been demonstrated to be involved in the senescence of BMSCs, which is one main cause of senile osteoporosis. These signaling pathways are activated by DNA damage or reactive oxygen species (ROS) accumulation and finally lead to cell senescence. Besides, BMP signaling and Wnt signaling also participate in inducing senescence of BMSCs by inducing ROS, triggering DNA damage or interacting with p53/p21 signaling. Moreover, epigenetic regulation also plays important role in regulating differentiation and senescence of BMSCs. The epigenetic regulation, such as DNA methylation and histone acetylation, regulates the differentiation and senescence of BMSCs by regulating the expression of transcription factors or disturbing the binding of transcription factors to specific gene's promoter. These findings provide an understanding of the molecular mechanisms underlying the altered differentiation and senescence of BMSCs during senile osteoporosis and provide potential targets or methods for treating senile osteoporosis.
Direct transplantation of normal BMSCs and elimination of senescent BMSCs both efficiently treat senile osteoporosis. Transplantation of normal allogeneic BMSCs into aged mice shows both prevention and treatment effects on senile osteoporosis. In addition, modification of the differentiation ability of BMSCs through targeting some genes can be applied for treating senile osteoporosis. More recently, elimination of senescent BMSCs has been demonstrated to be an effective therapeutic method for treating senile osteoporosis. All these findings strongly demonstrate that BMSCs can be applied for clinical treatment of senile osteoporosis by directly transplanting normal BMSCs, modifying differentiation of BMSCs, or eliminating senescent BMSCs. However, present findings are obtained from animal studies. Further clinical trials are needed.
Loss of Lung Function Correlates with Epigenetic Age Acceleration
Epigenetic clocks are a topic of considerable interest in the research community. They are perhaps the most promising of the present techniques for assessing biological age, the closest to becoming a useful biomarker of aging. Epigenetic clocks are weighted algorithmic combinations of the DNA methylation status of various sites on the genome, reflecting changes that are very similar for everyone, and which map to age with a margin of error of a few years. These changes are likely reactions to the growing damage and dysfunction of aging - and since everyone ages for the same underlying reasons, it makes sense for some of the changes that take place in cellular processes to be much the same for everyone. The initial epigenetic clocks are now being joined by many others, as there are any number of ways in which to create a viable combination of epigenetic marks that reflects aging.
The interesting aspect of an epigenetic age measure is the degree to which it is higher or lower than chronological age for a given individual. Acceleration of epigenetic age, a higher epigenetic age than chronological age, is quite robustly correlated with incidence of many age-related conditions, as well as with mortality risk. If aging is damage, then more damage has the expected outcome. Today's research materials, looking into lung function and epigenetic age, are illustrative of the numerous other correlational studies published in recent years.
The development of biomarkers of aging is an important topic. A low-cost way to quickly and rigorously measure the damage and dysfunction of age would greatly speed up research and development of rpotential rejuvenation therapies. At present, the only rigorous test of an approach to slow or reverse aging (versus treating a specific age-related condition) is a life span study. That is out of the question for human trials, and even in mice running a life span study is an expensive, slow proposition. As a result, researchers are beginning to use epigenetic age assessments in their studies of aging. Unfortunately, these tools are not yet finalized. Because it is unclear as to what exactly causes the characteristic epigenetic changes of age, it is unknown as to how an epigenetic clock will react to any given new class of ejuvenation therapy. The outcome of an assessment isn't yet actionable, whatever the result. The clocks will have to be calibrated and verified alongside rejuvenation therapies as they are developed - the results cannot yet be taken at face value.
Association of adult lung function with accelerated biological aging
Using longitudinal data from two population-based cohorts we have examined the association of lung function with epigenetic aging and shown that lung function is associated with measures of epigenetic age acceleration, particularly in women and with increasing age. Lung function decline is found to be strongly associated with increase in DNA methylation-based lifespan predictors, plasma protein levels, and their related age adjusted measures.
Our findings suggest that lung function is associated with age acceleration in women and particularly in women above age of 50 years. Forced expiratory volume in one second (FEV1) was found to be declining at a rate of 9.5 mL per year of age acceleration using regression between epigenetic and chronological ages (AAres) and 11.3 mL per year of age acceleration using intrinsic epigenetic age acceleration (IEAA). This same trend was observed for forced vital capacity (FVC). This observation was further supported by measures in an older group of women showing a greater effect of age acceleration on lung function decline.
When the association from the repeated measures from two time points was assessed, a marginal association was found in female subjects, showing a 3.94 ml decline in FVC per year of epigenetic age acceleration (AAres). In contrast, while measuring the effect of age acceleration on lung function decline between baseline and follow-up, there were no significant associations, suggesting that decline in lung function is proportional to the overall degree of biological aging.
In conclusion, this study suggests that epigenetic age acceleration is significantly associated with lung function in women older than 50 years. We hypothesised that this could be due to menopause. However, we have observed that menopause has minimal effect and therefore there is possibility of other unknown physiological factors at older age in females mediating the epigenetic age acceleration effect on lung function. While, it is still unknown what exactly epigenetic aging from DNA methylation measures, this study suggests it can be utilised as one of the important factors to assess women's lung health in old age. DNA methylation-based lifespan predictors, such as DNAm GrimAge and plasma protein levels are strongly associated with lung function. Therefore this study suggests that these can be utilised as important factors to assess lung health in adults.
Astrocyte Senescence Causes Death of Neurons in Cell Culture
With the caveat that the behavior of cells in culture is not necessarily all that relevant to their behavior amidst the full complexities of living tissue, this study is an interesting initial exploration of the ways in which the cellular senescence of supporting cells in the brain might contribute to the progression of neurodegeneration. Senescent cells secrete a potent mix of inflammatory and other signaling; while they serve a useful purpose when present for a short time, not all are successfully destroyed. Their numbers grow with age, and the presence of these errant cells and their signaling is very harmful over the long term. Thus the development of senolytic therapies to selectively destroy senescent cells is a very promising line of work in the treatment of aging as a medical condition.
Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemotherapy or radiotherapy. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies.
Among the essential cell types in the brain, astrocytes are the most abundant population. Astrocytes retain proliferative capacity, and their functions are crucial for neuron survival. Astrocytes are critical for mediating ion homeostasis, growth factor responses and neurotransmitter functions in the brain. Previous studies showed that astrocyte dysfunction is associated with multiple neurodegenerative diseases. Importantly, senescent astrocytes were identified in aged and Alzheimer's disease brain tissue, and other studies identified several factors that are responsible for inducing senescence in astrocytes. These studies reported a link between an inflammatory environment and neurodegenerative diseases, but how astrocyte senescence might alter brain function in general remains unclear.
Here, we investigated the phenotype of primary human astrocytes made senescent by irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Genes that regulate glutamate homeostasis as well as potassium ion and water transport are essential for normal astrocyte function. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.
Premature Menopause Correlates with Greater Later Incidence of Chronic Disease
Undergoing earlier menopause is a sign of a greater burden of age-related damage and dysfunction, so it should not be surprising to see that this correlates with a greater incidence of chronic disease in the years thereafter. People with a greater burden of cell and tissue damage tend to exhibit all of the manifestations of aging earlier than their less damaged peers. These variations in damage burden and consequences from individual to individual are near all the results of lifestyle choices, particularly smoking, weight, and exercise, and environmental factors such as exposure to chronic viral infection. Genetics plays only a small role until very late life, and even then it is outweighed by the choices made and the level of stress that the immune system has suffered over the years.
As life expectancy is now more than 80 years for women in high income countries, a third of a woman's life is spent after the menopause. It is known already that premature menopause, occurring at the age of 40 or younger, is linked to a number of individual medical problems in later life, such as cardiovascular disease and diabetes. However, there is little information about whether there is also an association between the time of natural menopause and the development of multiple medical conditions - known as multimorbidity.
Researchers used data on women who had joined the prospective Australian Longitudinal Study on Women's Health between 1946 and 1951. The women responded to the first survey in 1996 and then answered questionnaires every three years (apart from a two-year interval between the first and second survey) until 2016. The women reported whether they had been diagnosed with or treated for any of 11 health problems in the past three years: diabetes, high blood pressure, heart disease, stroke, arthritis, osteoporosis, asthma, chronic obstructive pulmonary disease, depression, anxiety, or breast cancer. Women were considered to have multimorbidity if they had two or more of these conditions.
During the 20 years of follow-up, 2.3% of women experienced premature menopause and 55% developed multimorbidity. Compared with women who experienced menopause at the age of 50-51 years, women with premature menopause were twice as likely to develop multimorbidity by the age of 60, and three times as likely to develop multimorbidity from the age of 60 onwards. "We found that 71% of women with premature menopause had developed multimorbidity by the age of 60 compared with 55% of women who experienced menopause at the age of 50-51. In addition, 45% of women with premature menopause had developed multimorbidity in their 60s compared with 40% of women who experienced menopause at the age of 50-51."
More on the SASP Atlas, a Basis for Biomarkers of Aging
In the publicity materials here, researchers discuss the recently published SASP Atlas, a fairly comprehensive map of the molecules secreted by senescent cells - the senescence-associated secretory phenotype (SASP). Cells become senescent at the end of their replicative lifespan, but also in response to wounding, DNA damage, a toxic environment, or the signals of senescent neighbors. Senescence is transient, in the sense that these cells should self-destruct or be destroyed by the immune system shortly after their creation. Unfortunately these processes become inefficient with age, leading to rising numbers of senescent cells throughout the body. When senescent cells are present in sizable numbers for long periods of time, the SASP becomes very harmful. It disrupts tissue function and produces chronic inflammation. It is an important contributing cause of aging.
Senescent cells, which stop dividing under stress, are long-recognized drivers of multiple diseases of aging. Mouse studies have shown that targeted removal of these cells and the inflammatory factors they secrete, known as the senescence-associated secretory phenotype (SASP), has beneficial results on multiple organ systems and functions. Success in the laboratory has given rise to companies and research projects aimed at developing either senolytics, drugs that clear senescent cells, or senomorphics, drugs that suppress the SASP. But drug development and clinical utilization require simple, reliable biomarkers to assess the abundance of senescent cells in human tissues.
Researchers have now extensively profiled the SASP of human cells and have generated a curated database available for use in the field, the SASP Atlas. "The stage is now set for the development of clinically-relevant biomarkers of aging. This will speed efforts to get safe and effective drugs into the clinic and, in the long term, could enable physicians to give patients a clear read-out of how well, or poorly, their various tissues and organs are aging. The complexity of the SASP, which is typically monitored by a few dozen secreted proteins, has been greatly underappreciated, and a small set of factors cannot explain the diverse phenotypes senescence produces in vivo."
The SASP Atlas as a comprehensive proteomic database of soluble and exosome SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins, but also includes a 'core' subset of proteins elevated in all SASPs. "For the first time we have the capability of measuring the burden of senescent cells in vivo and making educated guesses on how they became senescent and how neighboring cells are being affected."
A Conservative View on Lifestyle versus Pharmacological Interventions for Aging
This open access commentary reflects a reasonable conservative position on the development of means to treat aging, which is that nothing can yet produce greater and more reliable results in humans than undertaking a better lifestyle. In this view, some combination of aerobic exercise, strength training, and calorie restriction robustly does more for most people than any of the other options on the table. Ten years ago I would have agreed. Now, however, I think it clear that senolytic therapies to selectively destroy senescent cells and some forms of mesenchymal stem cell transplantation, those capable of produce a significant amount of engraftment of the transplanted cells, can achieve greater benefits than lifestyle choices. We would need to see more work on NAD+ upregulation and mitochondrially targeted antioxidants to make the same claim there, while much of the rest of the present field seems unlikely to ever do as well as lifestyle interventions.
In modern times, inventing a drug that prevents the aging-linked decline in organ function, expands the years of life spent in good health, or even increases lifespan promises fame and fortune for the discoverer. Vitamins, anti-oxidants, resveratrol and other alleged sirtuin activators, caloric restriction, nicotinamide adenine dinucleotide (NAD+) and its biosynthetic precursors, young blood and growth and differentiation factor 11 (GDF 11), senolytics, rapamycin and rapalogs, metformin as well as numerous other compounds and treatments all were (or still are) considered as the magic bullet for "anti-aging" effects in the last couple of years.
However, for most, if not all of them, preclinical results in animal models were difficult to translate to humans, unexpected adverse effects in animals or humans were reported, and/or clinical trials showing any efficacy in healthy young and old individuals are still elusive. Importantly, aging per se is not recognized as a disease, and so-called "anti-aging" effects are often difficult to disentangle from disease prevention. For example, it is not entirely clear whether the beneficial outcome of caloric restriction in non-human primates is due to a reduction of numerous diseases observed in control-fed primates (whatever control levels mean in a laboratory context for these animals), or if true "anti-aging" effects were achieved.
In stark contrast to the currently proposed putative "anti-aging" drugs, a combination of various lifestyle-based approaches clearly achieves the best epidemiological risk profile for healthy aging, with minimal or no adverse effects. Moreover, some of these approaches, for example exercise training, are not only highly efficient in preventing certain chronic diseases, but also in the treatment of numerous pathologies. While it is true that the molecular basis of the health beneficial effect of exercise remains largely enigmatic, for as long as data about clinical efficacy and safety of exercise "mimetics" and "anti-aging" drugs are missing (and probably even beyond that), lifestyle-based interventions remain the mainstay approach to minimize the risk for diseases, reduce morbidity and mortality and most importantly, improve healthspan in aging. The old adage "use it or lose it" should thus serve as a reminder that regular physical activity is directly and strongly linked to health in the young and the elderly.
Combination Gene Therapy for α-Klotho and TGFβR2 Improves Osteoarthritis in Mice
Researchers here report that upregulation of α-Klotho and TGFβR2 together, via gene therapy, can modestly reverse osteoarthritis in a rat model in which untreated animals progress to a more severe stage of the condition. Inhibiting TGF-β receptors such as TGFβR2 is known to suppress chronic inflammation, and likely functions by interfering in the inflammatory TGF-β signaling produced by senescent cells. The evidence for cellular senescence to drive the progression of osteoarthritis is quite compelling at this point. Meanwhile, α-Klotho declines with age and upregulation of this protein is known to improve regenerative capacity in some tissues.
Osteoarthritis is caused by gradual changes to cartilage that cushions bones and joints. During aging and repetitive stress, molecules and genes in the cells of this articular cartilage change, eventually leading to the breakdown of the cartilage and the overgrowth of underlying bone, causing chronic pain and stiffness. Previous research had pinpointed two molecules, αKLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs to treat osteoarthritis. αKLOTHO acts on the mesh of molecules surrounding articular cartilage cells, keeping this extracellular matrix from degrading. TGFβR2 acts more directly on cartilage cells, stimulating their proliferation and preventing their breakdown.
Researchers treated young, otherwise healthy rats with osteoarthritis with viral particles containing the DNA instructions for making αKLOTHO and TGFβR2. Six weeks after the treatment, rats that had received control particles had more severe osteoarthritis in their knees, with the disease progressing from stage 2 to stage 4. However, rats that had received particles containing αKLOTHO and TGFβR2 DNA showed recovery of their cartilage: the cartilage was thicker, fewer cells were dying, and actively proliferating cells were present. These animals' disease improved from stage 2 to stage 1, a mild form of osteoarthritis, and no negative side effects were observed.
Further experiments revealed 136 genes that were more active and 18 genes that were less active in the cartilage cells of treated rats compared to control rats. Among those were genes involved in inflammation and immune responses, suggesting some pathways by which the combination treatment works. To test the applicability of the drug combination to humans, the team treated isolated human articular cartilage cells with αKLOTHO and TGFβR2. Levels of molecules involved in cell proliferation, extracellular matrix formation, and cartilage cell identity all increased.
Senolytic Treatment Fails to Reverse Uterine Fibrosis in Mice
Senolytic drugs that selectively destroy senescent cells in aged tissues have performed quite well in animal studies of fibrosis in heart, lung, and kidney. The therapy reverses fibrosis in those tissues to a larger degree, and with greater reliably, than is the case for any other readily available approaches. Unfortunately small molecule senolytics are all tissue specific to varying degrees in their biodistribution and effects, and so the benefits are not universally realized throughout the body.
As an example of this point, researchers here show that uterine fibrosis and its consequences are unresponsive to dasatinib and quercetin senolytic treatment, though they do not determine whether the compounds reach the uterus to the same degree as is the case for the heart, lung, or kidneys. That leaves the question of exactly why this treatment is ineffective, poor biodistribution of the senolytics versus tissue-specific mechanistic differences in cellular senescence and fibrosis, to be answered at a later date.
The most obvious histological change in the aged uterus is the collagen deposition (fibrosis) in the muscle layers and stroma. Mechanisms involved in this uterine fibrosis remain unclear. Collagen deposition in tissues occurs as a result of chronic inflammatory processes involving several pathways: inflammatory interleukins, growth factors, caspases, oxidative stress products, and accumulation of senescent cells. Targeting senescent cells with senolytic drugs might slow down or prevent fibrosis processes in different tissues and organs. Currently, quercetin (Q) and dasatinib (D), administered alone or in combination (D+Q), are the most studied senolytic drugs. Different authors have reported anti-fibrotic effects of these drugs in tissues such as kidney, lung, and liver.
Studies about potential antifibrotic and senolytic effects of these drugs in the uterus are few, and there is no published study about effects of the D+Q combination on the uterus. It is important to mention that although these drugs alone have a senolytic potential, their combination selectively targets a broader range of senescent cell types than either agent alone. We investigated effects of aging and the senolytic drug combination of dasatinib plus quercetin (D+Q) on uterine fibrosis. Forty mice, 20 young females (03-months) and 20 old females (18-months), were analyzed.
The main morphological changes observed during the mice uterine aging were increased uterine volume and fibrosis. In our study, dilated uterus was observed in 35% of the old mice, with no cases observed in any young mice. Interestingly, the D+Q treatment did not reduce the prevalence of uterine dilatation in old mice. The main feature of the uterine fibrosis process is collagen deposition. Age-related fibrosis appears to be a slow and continuous process that might, over time, cause development of serious pathological complications, including those observed in our animals: a dilated uterus. Due to slow development of this age-related disease, D+Q senolytic therapy in the present protocol may not have been continued long enough for attenuating uterine collagen deposition.
Dicer1 Gene Therapy as a Treatment for Age-Related Macular Degeneration
Age-related macular degeneration is a common form of vision loss. It begins as a dry form, and progresses to a wet form as blood vessels inappropriately grow into damaged retinal tissue. Researchers have identified downregulation of Dicer1 as a factor in the progression of the condition, and here demonstrate that a gene therapy to increase expression of Dicer1 may form the basis for a therapy targeting both dry and wet stages of macular degeneration. That increased expression acts to block a significant cause of inflammation and cell death in retinal tissue.
Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown.
Deficiency of DICER1, an RNase that processes double-stranded and self-complementary RNAs including a majority of premature micro-RNAs (miRNAs) into their bioactive forms, is among the inciting molecular events implicated in atrophic AMD. DICER1 deficiency is implicated in RPE cell death in atrophic AMD due to accumulation of unprocessed Alu RNAs, which results in noncanonical activation of the NLRP3 inflammasome, an innate immune pathway resulting in RPE death.
We report that genetic suppression of Dicer1 in three independent mouse models manifests in the eye as focal RPE atrophy and aberrant choroidal and retinal neovascularization, and that DICER1 expression is reduced in a mouse model of spontaneous choroidal neovascular (CNV) lesions. Furthermore, we report that AAV-enforced expression of a DICER1 construct reduces spontaneous CNV in mice. In addition to expanding upon prior studies of DICER1 loss in atrophic AMD, these findings identify maintenance of outer retinal avascularity as another critical function of DICER1 in maintaining retinal homeostasis. This study also suggests that restoring DICER1 expression in the retina could itself be a viable therapeutic target for the treatment of AMD.
The Role of Lipids in Metastasis Offers Therapeutic Targets that May Work for Many Cancers
The primary mechanism by which most cancers kill patients is metastasis, the spread of cancerous cells from the original tumor to new locations throughout the body. If metastasis didn't exist, cancer would be a much more tractable problem, largely capable of being controlled via even the blunt approach of surgery. Research that might lead to ways to sabotage metastasis across many different types of cancer is thus of great interest. A number of possible approaches have emerged over the past decade or so, but none have as yet advanced to the point of practical application in the clinic.
Researchers have demonstrated that the most aggressive cancer cells use significant amounts of lipids as energy sources, and that cancer cells store lipids in small intracellular vesicles called 'lipid droplets'. Cancer cells loaded with lipids are more invasive and therefore more likely to form metastases. Researchers identified a factor called TGF-beta2 as the switch responsible for both lipid storage and the aggressive nature of cancer cells. Moreover, it appeared that the two processes were mutually reinforcing. In fact, by accumulating lipids, more precisely fatty acids, cancer cells build up energy reserves, which they can then use as needed throughout their metastatic course.
Already known was that the acidity found in tumours promotes cancer cells' invasion of healthy tissue. The process requires the detachment of the cancer cell from its original anchor site and the ability to survive under such conditions (which are fatal to healthy cells). The new finding: researchers demonstrated that this acidity promotes, via the same TGF-beta2 'switch', the invasive potential and formation of lipid droplets. These provide the invasive cells with the energy they need to move around and withstand the harsh conditions encountered during the process of metastatis.
Concretely, this research opens up new therapeutic avenues thanks to the discovery of the different actors involved in metastasis, as these actors can be targeted and combated. Researchers show that it is possible to reduce tumour invasiveness and prevent metastases using specific inhibitors of TGF-beta2 expression but also compounds capable of blocking the transport of fatty acids or the formation of triglycerides. Among the latter are new drugs that are being evaluated to treat obesity. Their indications could therefore be rapidly extended to counter the development of metastases, which is the major cause of death among cancer patients.
A Guide Implant Allows Regrowth of Inches of Lost Nerve Tissue
Severed nerves left with a significant gap between the ends do not regrow in adult mammals. Scarring rather than regeneration takes place, and loss of function is permanent. All is not bleak, however. Researchers here report on progress in guided nerve regrowth, using a implant that encourages regeneration of nerve tissue across a comparatively large distance. The prospects for recovery from damage to the peripheral nervous system are becoming brighter. Assuming it is accompanied by removal of scar tissue at the nerve ends, the regenerative approach illustrated here could, in principle, be applied well after an injury has taken place, and is thus particularly interesting.
Peripheral nerves can regrow up to a third of an inch on their own, but if the damaged section is longer than that, the nerve can't find its target. Often, the disoriented nerve gets knotted into a painful ball called a neuroma. The most common treatment for longer segments of nerve damage is to remove a skinny sensory nerve at the back of the leg - which causes numbness in the leg and other complications, but has the least chance of being missed - chop it into thirds, bundle the pieces together and then sew them to the end of the damaged motor nerve, usually in the arm. But only about 40 to 60% of the motor function typically returns.
Researchers have now created a biodegradable nerve guide - a polymer tube - filled with growth-promoting protein that can regenerate long sections of damaged nerves, without the need for transplanting stem cells or a donor nerve. The nerve guide returned about 80% of fine motor control in the thumbs of four monkeys, each with a 2-inch nerve gap in the forearm. The experiment had two controls: an empty polymer tube and a nerve graft. Since monkeys' legs are relatively short, the usual clinical procedure of removing and dicing a leg nerve wouldn't work. So, the scientists removed a 2-inch segment of nerve from the forearm, flipped it around and sewed it into place, setting a high bar for the nerve guide to match.
Functional recovery was just as good with the guide as it was with this best-case-scenario graft, and the guide outperformed the graft when it came to restoring nerve conduction and replenishing Schwann cells - the insulating layer around nerves that boosts electrical signals and supports regeneration. In both scenarios, it took a year for the nerve to regrow. The empty guide performed significantly worse all around.
Loss of Volume in the Cerebellum Correlates with Memory Decline with Age
The brain is known to shrink with age, by about 5% per decade in later adult life, though the underlying processes leading to this loss of volume are not well understood in detail. The research here adds to existing evidence for loss of volume to correlate with loss of cognitive function. It is unclear as to what can be done specifically to address this issue beyond developing the means to repair the list of damage and dysfunction that causes aging, and observing the results as repair therapies are deployed, first in animals, and then in humans.
The human cerebellum plays an essential role in motor control, is involved in cognitive function and helps to regulate emotional responses. However, little is known about the relationship between cerebellar lobules and age-related memory decline. We aimed to investigate volume alterations in cerebellar lobules at different ages and assess their correlations with reduced memory recall abilities.
A sample of 275 individuals were divided into the following four groups: 20-35 years (young), 36-50 years (early-middle age), 51-65 years (late-middle age), and 66-89 years (old). Volumes of the cerebellar lobules were obtained using volBrain software. Group differences in cerebellar lobular volumes were assessed, and multiple comparisons were used to investigate the relationship between lobular volumes and memory recall scores.
We found that older adults had smaller cerebellar volumes than the other subjects. Volumetric decreases in size were noted in bilateral lobule VI and lobule crus I. Moreover, the volumes of bilateral lobule crus I, lobule VI, and right lobule IV were significantly associated with memory recall scores. Thus some lobules of the cerebellum appear more predisposed to age-related changes than other lobules. These findings provide further evidence that specific regions of the cerebellum could be used to assess the risk of memory decline across the adult lifespan.