Fight Aging! Newsletter, July 29th 2019

Fight Aging! Newsletter, July 29th 2019

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  • More Evidence for Defects in the Formation of Autophagosomes to be Important in the Age-Related Decline of Autophagy
  • The Role of mTOR as a Regulator of Lifespan
  • p53, Hsp90β, and Cellular Senescence in Muscle Regeneration and Muscle Aging
  • Fat Cell Exosomes Demonstrated to Impair the Ability of Macrophages to Remove Cholesterol from Blood Vessel Walls
  • Commentary on the Developing UK Government Position on Healthy Longevity
  • Oxidative Stress in the Aging Brain Accelerates the Spread of α-synuclein
  • Myeloid Skew Arises from Age-Related Changes in Bone Marrow Niches
  • PGC-1α as a Target to Treat Age-Related Kidney Disease
  • Hippocampal Neurogenesis in Aging
  • Investigating the Mechanisms of FOXO3 Effects on Longevity
  • A Consistent Transcriptomic Signature of Cellular Senescence
  • An Interview with María Blasco on Telomeres and Telomerase
  • GM1 Reduces Aggregation of α-Synuclein in an Animal Model of Parkinson’s Disease
  • Damage to Lymphatic Vessels Impairs Drainage of Cerebrospinal Fluid with Age
  • Reversing Somatic Mosaicism in Aged Tissue

More Evidence for Defects in the Formation of Autophagosomes to be Important in the Age-Related Decline of Autophagy

Autophagy is a collection of cellular maintenance processes that act to recycle damaged structures in the cell, thereby maintaining cell health and function. On the one hand, the efficiency of autophagy declines with age, and this loss of function is associated with numerous age-related diseases, particularly of the central nervous system and its population of very long-lived neurons. On the other hand, increased autophagy is an important component of many of the interventions shown to slow aging in short-lived species, such as via calorie restriction. A fair number of research groups are working on ways to upregulate autophagy in our species, but this has been going on for a while with little concrete movement towards the clinic.

Autophagy is a complicated process of multiple steps, and at every step there are plausible proximate causes for a faltering of the system with age. The formation of autophagosomes to encapsulate materials to be recycled can break down, as is the case in today’s open access paper. The mechanisms by which autophagosomes are transported to a lysosome for deconstruction of their contents are degraded. The lysosome itself becomes filled with metabolic waste that it struggles to break down, making it bloated and inefficient.

In the case of defects relating to autophagosomes it is unclear as to why the breakage happens, how it relates to the underlying molecular damage that causes aging. Given this, approaches to therapy tend to focus on overriding proximate changes. Researchers find regulatory systems that can be adjusted in order to force the relevant mechanism to work despite its normal reaction to systemic damage in and around cells. In principle this should always be worse as a strategy than identifying and repairing the damage, but it can produce benefits in some cases. In the example here, researchers find a way to override the failure to form autophagosomes that is observed in old neurons.

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

Unlike most of the cells in our body, our neurons are as old as we are: while other cell types are replaced as they wear out, our neurons must last our entire lifetime. The symptoms of disorders such as Alzheimer’s disease and ALS result from neurons in the brain or spinal cord degenerating or dying. But why do neurons sometimes die?

One reason may be that elderly neurons struggle to remove waste products. Cells get rid of worn out or damaged components through a process called autophagy. A membranous structure known as the autophagosome engulfs waste materials, before it fuses with another structure, the lysosome, which contains enzymes that break down and recycle the waste. If any part of this process fails, waste products instead build up inside cells. This prevents the cells from working properly and eventually kills them.

Aging is the major shared risk factor for many diseases in which brain cells slowly die. Could this be because autophagy becomes less effective with age? Researcher isolated neurons from young adult, aging and aged mice, and used live cell microscopy to follow autophagy in real time. The results determined that autophagy does indeed work less efficiently in elderly neurons. The reason is that the formation of the autophagosome stalls halfway through. However, increasing the amount of one specific protein, WIPI2B, rescues this defect and enables the cells to produce normal autophagosomes again.

As long-lived cells, neurons depend on autophagy to stay healthy. Without this trash disposal system, neurons accumulate clumps of damaged proteins and eventually start to break down. The results identify one way of overcoming this aging-related problem. As well as providing insights into neuronal biology, the results suggest a new therapeutic approach to be developed and tested in the future.

The Role of mTOR as a Regulator of Lifespan

The mTOR gene is deeply involved in the regulation of cellular activities in response to nutrient sensing. It is also implicated in the many, many changes that occur to slow aging in response to a restricted calorie intake, including processes known to be important to aging such as mitochondrial function and cellular senescence. Given that most research to date on intervention in the aging process has focused on the calorie restriction response and related upregulation of stress response mechanisms, it is no surprise that mTOR has attracted a lot of attention. The first mTOR inhibitor drugs are already going through clinical trials, developed by companies such as resTORbio and Navitor Pharmaceuticals.

It is unfortunate that this strategy for modulating the pace of aging has far larger effects on life span in short-lived species than in long-lived species such as our own: calorie restriction extends life by 40% in mice, but by no more than a few years for us. This is thought to be a consequence of the seasonal nature of famine. A famine lasts a large fraction of a mouse life span, but very little of a human life span, so only the mouse has the evolutionary pressure to develop a large plasticity of life span in response to calorie restriction.

The end result of these factors is that upregulation of stress response mechanisms just doesn’t do as much in our species as it does in mice, or in any other short-lived laboratory species. Thus we shouldn’t expect therapies targeting mTOR to do much more than can already be achieved via the practice of calorie restriction. That means some degree of improved health, as illustrated in clinical trials for immune function in later life, for example, but no great extension of life span.

mTOR as a central regulator of lifespan and aging

Consistent with its role in coordinating protein synthesis, energy metabolism, and autophagy in cancer, emerging evidence suggests that mTOR may act as a central node that orchestrates many aspects of cellular and organismal biology related to aging phenotypes. Inhibition of the mTOR pathway by rapamycin or genetic means has profound effects on life span and age-associated phenotypes across a wide array of organisms. However, the underlying mechanisms are still unclear as it has been reported that during aging mTOR activity is both increased and decreased, depending on, for example, tissue or sex. It was suggested that, in spite of these variations, overall aging does not result in a generalized increase in mTOR signaling. If this is the case, it is possible that mTOR activity aligns with the antagonistic pleiotropy theory of aging, whereby its levels are beneficial during development but limit the health span in adult life.

Owing to its central role in age-related processes, mTOR represents an appealing target to ameliorate age-related pathologies. Despite its capacity to expand life span, the function of rapamycin (and of rapalogs) as an immunosuppressant might be of concern, as a decline in immune function (immunosenescence) already occurs in the elderly, leading to infection-related morbidity and mortality. Intriguingly, several studies in both mice and humans suggest that mTOR inhibitors could reduce immunosenescence. In mice, rapamycin can restore the self-renewal and hematopoiesis of hematopoietic stem cells and enable effective vaccination against the influenza virus. A randomized trial testing the effects of rapalog RAD001 in a cohort of healthy elderly patients also showed an enhanced response to the influenza vaccination.

Another limitation of rapamycin is that its chronic exposure in mice leads to mTORC2 inhibition in, for example, hepatocytes. Active-site mTOR inhibitors also inhibit mTORC2. Strikingly, selective suppression of mTORC2 reduces life span and is associated with changes in endocrinology and metabolism (for example, insulin resistance), which have a negative impact on health span. Thus, developing specific inhibitors which effectively suppress all mTORC1 outputs, but do not exert a major effect on mTORC2, appears to be warranted as a strategy to target age-related pathologies and improve health span. Interestingly, in a recent trial of healthy elderly patients, the combination of low-dose RAD001 (rapalog) and BEZ235 (dual mTOR/PI3K catalytic inhibitor) was proposed to selectively inhibit mTORC1 and not mTORC2 and led to enhanced immune function and a reduction in infections. However, it is important to note that complete inhibition of mTORC1 can be deleterious.

Biguanides (for example, metformin) are pharmaceuticals which are thought to have a beneficiary effect (in aging) that indirectly impinges on mTOR. Metformin is a first-line anti-diabetic drug which has been used for more than 60 years in the clinic and has very few side effects. It was shown to modulate life span in model organisms, to affect several processes dysregulated in aging (for example, cellular senescence, inflammation, autophagy, and protein synthesis), and to improve cognitive function and neurodegeneration in humans. By inhibiting mitochondrial complex I, metformin causes energetic stress which results in mTORC1 inhibition through AMPK-dependent and independent mechanisms.

Although many studies have uncovered possible targets of metformin action in the cell in the context of aging, the full extent of metformin’s mechanism of action at the cellular and organismal levels is still incompletely understood. Nonetheless, clinical trials in which metformin is used to improve health span or aging-related conditions are being proposed. For instance, in the TAME (targeting aging with metformin) clinical trial, a placebo-controlled multi-center study of about 3000 elderly patients who are 65 to 79 years old, the effects of metformin on the development of age-associated outcomes like cardiovascular events, cancer, dementia, and mortality will be monitored.

p53, Hsp90β, and Cellular Senescence in Muscle Regeneration and Muscle Aging

Senescent cells are a mechanism of aging, but also a mechanism of regeneration. When entering a senescent state, a cell shuts down replication and begins to secrete a mix of inflammatory and other signals, rousing the immune system and altering the behavior of surrounding cells. In addition to the other ways in which cells become senescent, in response to the Hayflick limit on cellular replication, or to potentially cancerous DNA damage, senescent cells also arise in response to injury. Their secretions help to guide the complicated dance of immune cells, stem cells, and somatic cells that takes place during the consequent regeneration. Afterwards, the senescent cells self-destruct via apoptosis, or are destroyed by the immune system.

Unfortunately, it is never the case that all senescent cells are destroyed. Those resulting from injury are a tiny fraction of the somatic cells that become senescent on reaching the Hayflick limit, but we can still hypothesize that cellular senescence is important in, say, the way in which joint injuries can become lasting disabilities, or bring on early arthritis. As lingering senescent cells accumulate in tissues, secreted signals that are beneficial in the short term become instead the cause of chronic inflammation and disruption of normal tissue function. Senescent cells are thus a cause of aging, and we will all benefit from therapies capable of removing those that linger in our bodies.

Today’s open access paper is an example of the widespread and ongoing deeper investigations of the biochemistry of senescent cells. The present growth of a biotechnology development community focused on producing therapies to destroy senescent cells helps to ensure that ever more funding is provided for fundamental research. In the present environment any novel examination of cellular senescence might turn up mechanisms that can give rise to startup biotechnology companies, which tends to encourage more such research. In this case the focus is on one of the many protein interactions underlying the behavior of senescent cells in muscle regeneration and aging.

Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration

Skeletal muscle acts as a key regulator of systemic aging in humans. The negative effects of senescence on skeletal muscle were recognized since loss of muscle mass during aging results in frailty and decrease in life qualify. Reduction of quiescent muscle stem cells through senescence leads to the decline in muscle regeneration in aged mice. It is noteworthy that the senescence-associated secretory phenotype (SASP) plays a key role in regulating the beneficial action of senescence during tissue regeneration.

Notably, transient, but not aberrant or prolonged, exposure to the SASP enhances stemness and induces cell plasticity, both of which are beneficial for regeneration. However, a p53-dependent persistent senescence impairs muscle repair, indicating that the accurate temporal regulation of p53-induced senescence is pivotal for ensuring accomplishment of muscle regeneration. Interestingly, a recent report showed that activated Notch-p53 is important for the expansion of muscle stem cell in aged animal. Moreover, p53 also regulates the balance between myoblast differentiation and quiescence. These findings indicate that the roles of p53 in modulating muscle homeostasis are complicated.

Here, we found that Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90β-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90β interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90β in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo.

Fat Cell Exosomes Demonstrated to Impair the Ability of Macrophages to Remove Cholesterol from Blood Vessel Walls

Carrying excess visceral fat tissue, the fat packed around organs in the abdomen, accelerates all of the common conditions of aging. This is most likely largely mediated by chronic inflammation, the overactivation of the immune system that fat tissue produces. Numerous mechanisms contribute to this inflammation: fat tissue generates an outsized number of lingering senescent cells that secrete inflammatory signals; dying fat cells produce DNA debris that triggers an immune response; fat cells burdened by a lot of lipids generate similar signals to those released by infected cells; and so forth.

Chronic inflammation is particularly important in the progression of atherosclerosis. Cholesterols in the bloodstream find their way into blood vessel walls, and must be removed by the innate immune cells known as macrophages, which hand off the cholesterol to high-density lipoprotein (HDL) particles for it to be carried back to the liver for excretion. With age, rising levels of inflammation and oxidative stress generate ever more oxidized cholesterols, and these damaged molecules, particularly 7-ketocholesterol, cause macrophages to become dysfunctional. Further, chronic inflammation causes macrophages to act inappropriately, becoming inflammatory themselves rather than usefully engaging in removing cholesterol from blood vessel tissue. The result is fatty lesions, formed of cholesterols and the debris of dead macrophages, overwhelmed trying to help. The more inflammatory signaling there is, the more macrophages are called in to their doom.

In the research results I’ll point out today, scientists have found another way in which fat tissue can degrade the ability of macrophages to remove cholesterol from blood vessel walls, operating independently of inflammatory mechanisms. Exosomes, a form of membrane-bound extracellular vesicle packed with signal molecules, are released by fat cells and, when taken up by macrophages, impair the ability of those macrophages to carry out the action of passing a cholesterol molecule to an HDL particle. While the study was carried out in young people, I would expect the mechanism to operate in older individuals as well. There are already countless very good reasons to avoid becoming fat: it is arguably the case that being overweight literally accelerates the aging process. Nonetheless, here is another one.

MicroRNAs from human fat cells can impair macrophage ability to eliminate cholesterol

In atherosclerosis, blood vessels that carry oxygen-rich blood throughout the body become inflamed, and macrophages settle in the vessel wall and become overloaded with cholesterol. A plaque forms that restricts blood flow. But it remains a mystery how fat cells residing in one place in the body can trigger mayhem in cells and tissues located far away. Extracellular vesicles (EVs) seemed likely troublemakers since they enable intercellular communication. “We found that seven specific small sequences of RNA (microRNA) carried within the extracellular vesicles from human fat tissue impaired the ability of white blood cells called macrophages to eliminate cholesterol. Fat isn’t just tissue. It can be thought of as a metabolic organ capable of communicating with types of cells that predispose someone to develop atherosclerotic cardiovascular disease, the leading cause of death around the world.”

Because heart disease can have its roots in adolescence, the researchers enrolled 93 kids aged 12 to 19 with a range of body mass indices (BMIs), including the “lean” group, 15 youth whose BMI was lower than 22 and the “obese” group, 78 youths whose BMI was in the 99th percentile for their age. Their median age was 17. Seventy-one were young women. The researchers collected visceral adipose tissue during abdominal surgeries. “We were surprised to find that EVs could hobble the macrophage cholesterol outflow system in adolescents of any weight. It’s still an open question whether young people who are healthy can tolerate obesity – or whether there are specific differences in fat tissue composition that up kids’ risk for heart disease.”

Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide. Although primarily a disease of adults, youth with obesity show evidence of subclinical ASCVD which places them at increased risk as adults for coronary heart disease and stroke. The mechanisms by which obesity confers cardiovascular risk are not fully understood, but inflammation within visceral adipose tissue (VAT) is thought to be contributory. Further, the impact of excess adipose tissue on distal sites such as arterial wall monocytes/macrophages, direct participants in ASCVD, are also thought to contribute to disease pathogenesis.

In this study we show, for the first time, significant alterations in cholesterol efflux capacity in adolescents throughout the range of BMI, a relationship between six circulating adipocyte-derived EVs microRNAs targeting ABCA1 and cholesterol efflux capacity, and in vitro alterations of cholesterol efflux in macrophages exposed to visceral adipose tissue adipocyte-derived EVs acquired from human subjects. These results suggest that adipocyte-derived EVs, and their microRNA content, may play a critical role in the early pathological development of ASCVD.

Commentary on the Developing UK Government Position on Healthy Longevity

One option for patient advocacy for the treatment of aging as a medical condition is to petition governments and large international organizations such as the World Health Organization to adjust their positions on research funding and goals in medicine. This a fairly popular path, for all that I think it not terribly effective at speeding up the cutting edge of research and development. Large organizations of any sort are inherently conservative, and tend to get meaningfully involved in new fields of human endeavor only long after their support would have been truly influential.

Nonetheless, numerous examples of government focused initiatives have emerged from our community over the past decade. They include the Longevity Dividend initiative, petitioning the US government for greater public funding for translational aging research; the small single issue political parties focused on longevity in Germany, Russia, and elsewhere; efforts to influence the contents of the International Classification of Diseases produced by the World Health Organization, in order to classify aging as a disease; and so forth. In recent years, an informal collaboration between advocates, investors, and others in the UK has been making inroads into influencing thinking on aging and longevity in government circles in that country. One of their successes is noted here.

Success, yes, and somewhat more than has been achieved elsewhere. Nonetheless, progress in these efforts in any part of the world tends to be painfully slow and incremental. Persuading bureaucrats to think about making a formal goal of the addition of just a few years to life expectancy over the next few decades is considered a victory. But this is far too little. We live now in an era of biotechnology in which much larger gains in life expectancy are possible and plausible given sufficient investment in research and development. The implementation of rejuvenation therapies, of which senolytic treatments to clear senescent cells are only the first, will up-end all these minor expectations of a few years here and a few years there. That should be the goal.

UK Government Prioritizes Healthy Longevity as a Major National Priority in New Green Paper

This week the UK Government published the green paper of its Preventive Medicine National Strategy, entitled “Advancing our health: prevention in the 2020s – consultation document”. In practice, this indicates that the UK will be the first country to officially implement P4 (Personalized, Preventive, Precision and Participatory) medicine into its national healthcare system.

This is the newest development in a series of large steps that the UK government has made in recent years towards the development of a proactive, progressive and technology-driven national Healthy Longevity development strategy, beginning with the formation of the Ageing Industrial Grand Challenge (prioritizing the problem of ageing population as one of four key national industrial development challenges for the nation) in 2017, followed by the launch of the 98 million Government-led Healthy Ageing Industrial Strategy Challenge Fund in 2018, and the launch of the All-Party Parliamentary Group for Longevity in 2019.

These are some of the major factors that led to the UK being ranked first in Aging Analytics Agency’s National Longevity Development Plans analytical report, which used quantitative metrics to rank the strength, proactivity and relevance of various nations’ Longevity development projects and initiatives.

Advancing our health: prevention in the 2020s – consultation document

Thanks to developments in public health and healthcare, we’ve made great progress in helping people to live longer lives. For example, life expectancy has increased by almost 30 years over the past century. Cancer survival rates are up and mortality rates from heart disease and stroke are down. However, these improvements in life expectancy are beginning to slow, and over 20% of years lived are expected to be spent in poor health.

Last year, the government set a mission as part of the Ageing Society Grand Challenge to “ensure that people can enjoy at least 5 extra healthy, independent years of life by 2035, while narrowing the gap between the experience of the richest and poorest”. The green paper proposals will not deliver the whole ‘5 years’. But they will help us towards achieving this mission. Further details on this will be provided later in the year, through a government response to the green paper.

Oxidative Stress in the Aging Brain Accelerates the Spread of α-synuclein

Parkinson’s disease, like many neurodegenerative conditions, is associated with the age-related aggregation of a specific protein, in this case α-synuclein. The protein aggregates have a halo of harmful biochemistry, causing dysfunction and cell death in neurons. Researchers here propose that the increased levels of oxidative stress observed in old tissues spur the spread of α-synuclein protein aggregates from cell to cell as the disease progresses. Oxidative stress can arise from mitochondrial dysfunction, as mitochondria produce oxidative molecules as a byproduct of their normal operation, but is also associated with chronic inflammation. Both are also features of aging and thought to be important in the progression of neurodegenerative conditions.

At the microscopic and pathological levels, Parkinson’s disease is characterized by accumulation of abnormal intraneuronal inclusions. They are formed as a result of aggregation of a protein called α-synuclein. In the course of the disease, these inclusions progressively appear in various brain regions, contributing to the gradual exacerbation of disease severity. The mechanisms behind this advancing pathology are poorly understood. Research now indicates that oxidative stress, i.e. an excessive and uncontrolled production of reactive oxygen species, could play an important role in the pathological spreading of α-synuclein.

In a series of experiments, researchers studied mice that overproduced α-synuclein in a specific brain region, namely the dorsal medulla oblongata, known to be a primary target of α-synuclein pathology in Parkinson’s disease. Under this condition, the researchers were able to show oxidative stress, formation of small α-synuclein aggregates (so called oligomers) and neuronal damage. Increased production of α-synuclein also led to its “jump” from donor neurons in the medulla oblongata into recipient neurons in neighboring brain regions that became affected by progressive α-synuclein accumulation and aggregation.

Interestingly, treatment of mice with paraquat, a chemical agent that generates substantial amounts of reactive oxygen species and thus triggers an oxidative stress, exacerbated α-synuclein pathology and resulted in its more pronounced spreading throughout the brain. “Our findings support the hypothesis that a vicious cycle may be triggered by increased alpha-synuclein burden and oxidative stress. Oxidative stress could promote the formation of alpha-synuclein aggregates which, in turn, may exacerbate oxidative stress. Jumping from neuron to neuron, this toxic process could affect more and more brain regions and contribute to progressive pathology and neuronal demise.”

Myeloid Skew Arises from Age-Related Changes in Bone Marrow Niches

Hematopoietic stem cells (HSCs) resident in bone marrow generate immune cells, and their activity is thus vital to the correct function of the immune system. Like all stem cell populations, HSCs are sustained by a niche of supporting cells. One of the interesting questions relating to the aging of stem cells and the decline of stem cell activity in later life is whether this is a problem inherent to the stem cells themselves, or it arises from change and damage in the niche. There is evidence for both to be the case, but it is possible to argue that, until extreme old age, the loss of activity is more a matter of the niche than actual incapacity on the part of stem cells.

One of the ways in which HSC behavior changes with age, and that alters the immune system for the worse, is that ever more myeloid and ever fewer lymphoid daughter cells are created. This myeloid skew is a well studied phenomenon, but as for all complex systems in the body, the causes and their relations to one another are much debated. Here, researchers discuss some specific mechanisms in the HSC niches in the bone marrow that may contribute to this phenomenon.

Hematopoietic aging is characterized by expansion of hematopoietic stem cells (HSCs) with impaired function, such as reduced engraftment, quiescence, self-renewal, unfolded protein response, and lymphoid differentiation potential, leading to myeloid-biased output both in mice and humans. Myeloid malignancies are more frequent in the elderly, but whether changes in the aged HSCs and/or their microenvironment predispose to these malignancies remains unclear.

Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological or natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the bone marrow microenvironment promotes myelopoiesis in premature and physiological aging.

During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased bone marrow noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal or premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.

PGC-1α as a Target to Treat Age-Related Kidney Disease

The research reviewed here is a great example of the presently dominant paradigm in efforts to treat age-related disease. Scientists analyze the disease state, find regulator proteins that are differently expressed in normal and diseased tissue, and look for ways to force expression in diseased tissue to look more like that of normal tissue. There is no consideration of trying to fix the underlying molecular damage that caused this change. It is a little like pressing the accelerator harder in a car with a failing engine. This strategy is why most efforts to treat age-related disease in the past have either failed or produce only minor benefits. Without fixing the underlying damage, it will continue to cause all of the downstream consequences that lead inexorably to failure of tissue function and death.

Aging is a progressive disruption of the homeostasis of physiological systems with age. It results in structural destruction, organ dysfunction, and increased susceptibility to injuries and diseases. The kidney is one of the most susceptible organs to aging. Aging-associated complications can lead to kidney dysfunction, including a decreased glomerular filtration rate, tubular dysfunction, and glomerulosclerosis. Furthermore, kidney aging has important implications for aging-associated comorbidities, especially cardiovascular diseases.

While the molecular mechanism underlying kidney aging remains unclear, chronic kidney disease (CKD) shares many phenotypic similarities with aging, including cellular senescence, fibrosis, vascular rarefaction, loss of glomeruli, and tubular dysfunction. The pathogenic mechanisms involved in CKD may thus provide insight into the molecular pathways leading to kidney aging. They might also provide potential targets against kidney aging.

Recent efforts to overcome aging have shifted from the discovery of risk factors to the determination of endogenous protective factors that might neutralize the adverse effects of aging. Among the various endogenous protective factors reported are AMP-activated protein kinase (AMPK), fibroblast growth factor 21 (FGF21), insulin, and vascular endothelial growth factor (VEGF).

Recent studies have shown that aging-related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose metabolism and lipid metabolism. PGC-1α is abundant in tissues, including kidney proximal tubular epithelial cells, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC-1α by genetic or pharmacological means prevents telomere shortening and aging-related changes in the skeletal muscle, heart, and brain. The activation of PGC-1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC-1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.

Hippocampal Neurogenesis in Aging

In at least some portions of the brain, new neurons are created throughout life in a process called neurogenesis. This is vital to memory and learning, but declines with age. Faltering neurogenesis is arguably implicated in the development of some neurodegenerative conditions. As most of the evidence for neurogenesis in adult individuals has been established in mice, and in recent years there has been some debate over whether or not these same processes do in fact operate in humans. So far, the most recent evidence leans towards supporting the existence of human adult neurogenesis. Given this, the research community remains interested in developing means of increasing the pace of neurogenesis as a basis for therapies to enhance cognitive function in the old, but progress towards this goal remains slow.

Adult hippocampal neurogenesis has been proposed to be a key element in ensuring and maintaining functional hippocampal integrity in old age. Neurodegenerative diseases due to the age-dependent rapid and continuous loss of neurons (such as Parkinson’s disease and Huntington’s disease) have been suggested to reflect the contraposition of the neurogenic process such that under homoeostatic conditions a fine balance between neurodegeneration and neuroregeneration exists, and under pathological conditions, the balance is disturbed and a disease manifests. Even though little evidence has accumulated in support of this theory, if it proves correct, it in combination with findings regarding the high potential of stem-cell-based strategies for the treatment of age-related neurodegenerative disorders, make the hypothesis that adult neurogenesis holds a key to novel therapeutic approaches in the treatment of age-related neurodegenerative disorders rather attractive.

Decreased hippocampal neurogenesis is proposed as an important mechanism underlying age-related cognitive decline as well as neurodegenerative disorders such as Alzheimer’s disease (AD) and various types of dementia. Evidence in this regard was recently published in two separate recent studies examining hippocampal neurogenesis in human tissue from people suffering mild cognitive impairment and AD. Both studies demonstrated a dramatic decrease in the number of neural progenitor cells and neuroblasts in hippocampal tissue from AD patients which was related to the stage of the disease. Interestingly, a decrease in the number of newborn neurons was observed in AD patients at the very early stage of the disease when the characteristic neurofibrillary tangles and senile plaques had not become prevalent. This suggests a potential for using neurogenesis levels as an early biomarker of the disease.

The mechanisms underlying the age-related decline in hippocampal neurogenesis remain poorly understood. It has been proposed that within the senescent brain the neurogenic niche may be deprived of the extrinsic signals regulating the neurogenic process or that the aged neural progenitor cells are less responsive to normal signalling within the niche, or both. The evidence accumulated thus far points to changes in the properties of the neurogenic niche with age, rather than changes in the phenotype of the stem cells or progenitor cells themselves. For instance, it has been reported that the numbers of neural stem cells and neural progenitor cells as well as the proportion of astrocytes to neurons in the hippocampus of young and aged rats remained the same; however, there was a decrease in the number of cells actively undergoing mitosis in the aged animals.

Investigating the Mechanisms of FOXO3 Effects on Longevity

The relationship between normal genetic variations and consequence differences in life expectancy is enormously complex. Countless genetic variations have tiny, contingent, interacting effects on health and late life resilience to the damage of aging. Correlations found in epidemiological studies are rarely replicated between study populations. FOXO3 is one of the very small number of genes for which effects on longevity are found in multiple species and human populations. These effects are not large: a modestly increased chance of living longer. It is also worth noting recent research that downgraded the expected size of effect for FOXO3 based on more rigorous assessment of data. Here, researchers discuss some of the low-level mechanisms that might explain this association.

Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs.

FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes.

Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.

A Consistent Transcriptomic Signature of Cellular Senescence

As numerous senolytic therapies to clear senescent cells continue their progress towards the clinic, the research and development communities find themselves in ever greater need of better biomarkers for cellular senescence. Those that presently exist, such as staining tissue samples for senescence-associated β-galactosidase, are good enough for much of the present scope of research use, but not a suitable basis for either clinical assays or more sophisticated investigation of the mechanisms of senescence. As (a) there are numerous paths by which cells become senescent, prompted by different circumstances, and (b) senescence may vary in other ways between tissue types, and (c) different senolytics have different degrees of effectiveness across these varied classes and cells, it is the case that better and more consistent biomarkers would help to speed progress in this field.

Senescence is a state of indefinite growth arrest. It can be induced by various sublethal stresses, including telomere shortening, genomic injury, epigenomic damage and signaling from oncoproteins. Senescence is also characterized by a senescence-associated secretory phenotype (SASP) whereby cells produce and secrete pro-inflammatory cytokines. Senescence is beneficial for tissue remodeling, embryonic development, wound healing, and tumor suppression in young individuals. However, in old individuals it promotes aging-associated declines and diseases.

Progress to identify senescent cells in order to exploit them therapeutically has been hampered by a lack of robust and universal measurable traits. Thus far, senescence has been studied in a range of cell types induced by diverse triggers such as replicative exhaustion, DNA damage, oxidation and other stress conditions like signaling through oncoproteins. Due to this heterogeneity, finding broad biomarkers of senescence has been challenging and senescent cells are currently found through the combined detection of multiple biochemical markers such as p16, p53, p21 and SA-βGal, despite the fact that they are not exclusively nor consistently induced in senescence.

In this study, we sought to identify universally expressed transcripts across various senescent cell models. We performed RNA sequencing (RNA-seq) analysis after triggering senescence in human WI-38 and IMR-90 fibroblasts, human umbilical vein endothelial cells (HUVECs) and human alveolar endothelial cells (HAECs) through replicative exhaustion (WI-38, IMR-90), exposure to ionizing radiation (WI-38, IMR-90, HUVEC, HAEC) or doxorubicin (WI-38) or expression of an oncogene (oncogene-induced senescence, OIS) (WI-38). Comparisons of all the patterns of expressed transcripts revealed 68 RNAs that were increased (50 RNAs) or decreased (18 RNAs) across all senescence models, although a mimimum of 5 RNAs were sufficient to identify senescent cells bioinformatically. Most RNAs altered during senescence were protein-coding transcripts, but the long non-coding RNA PURPL (p53-upregulated regulator of p53 levels) was one of the most strikingly elevated transcripts.

An Interview with María Blasco on Telomeres and Telomerase

The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed María Blasco, on the occasion of her presentation at the Ending Age-Related Diseases conference in New York earlier this month. Blasco is one of the leading researchers in the field of telomere biology, particularly the role of telomerase and the prospects for developing telomerase gene therapies to slow aging by lengthening telomeres globally throughout the body. This should have the effect of putting damaged cells back to work, resulting in better tissue maintenance and function, but quite possibly at the cost of increased cancer risk.

Telomerase gene therapy works to achieve this goal in mice, extending life and actually reducing cancer risk, possibly because of improved immune suppression of cancer overwhelming any increased generation of cancerous cells. There is some debate over whether or not the same approach will be safe in humans. Humans and mice have very different telomere dynamics, and the balance of effects may or may not be similar. It seems likely that we’ll find out the direct way as human trials and clinical therapies become more widespread over the next decade.

You and your team recently showed that it is the rate of telomere shortening that predicts the lifespan of a species rather than the total length of telomeres. Does this discovery confirm the role of telomere attrition as a primary cause of aging rather than a consequence?

I think this study that means that telomeres are important in determining a species’ longevity. It’s not something that happens only in humans, where it’s already clear that in humans, telomere length matters, because there are humans that have mutations in telomerase, and they are going to have diseases associated with telomere shortening, which means that telomere shortening rates are very limiting for humans. We didn’t know whether this was general to other species or only something particular to humans. In this study, we see that telomeres seem to matter across evolution in different species, from birds to mammals. It’s not the telomere length that matters but the rate of telomere shortening. So, we see that the rate of telomere shortening actually fits into a power law curve, and this predicts the longevity of a given species.

Could it mean that telomere shortening rate could be a suitable aging biomarker to test interventions against aging with?

I think so; telomere shortening rate is important in humans in order to determine if anyone is at risk of prematurely developing diseases associated with short telomeres. It’s not as important to measure telomeres once, because this probably is not going to be very informative, but the rate at which telomeres shorten may be more informative of the risk of developing any disease related to short telomeres.

Telomerase has many effects that are independent of telomeres. Can you see that they matter in aging?

Well, it is interesting because we have, in the past, demonstrated that we can extend the lifespan of mice by using telomerase, but it must be wild-type telomerase; if we use catalytically dead telomerase, then we don’t see this lifespan extension. So I would say that in order to see effects of telomerase in lifespan, you need it to be catalytically active telomerase, and this is the canonical pathway of telomerase, which is elongating the telomeres. At least in our hands, this is the mechanism by which telomerase can increase longevity: by extending short telomeres.

Would you say that the telomere mechanisms and the dynamics are really that different between mice and people?

I think humans and mice are not that different. What is very different is the rate at which mice experience shortening telomeres, or in other words, mice are much worse than humans at maintaining their telomeres. So, I think this makes a difference. So mice shorten their telomeres really fast, we still don’t understand why compared to humans, but now we also know that different species shorten their telomeres at different rates, and I think it’s very interesting to study that. We don’t know why. For example, the elephant and the flamingo have the same rate of telomere shortening and they have similar longevity; why is that? Then a mouse has a much faster rate of telomere shortening and a shorter longevity. I think this is a very interesting question to solve in the future.

GM1 Reduces Aggregation of α-Synuclein in an Animal Model of Parkinson’s Disease

Parkinson’s disease, like most other neurodegenerative conditions, is characterized not just by chronic inflammation and cell death, but also by protein aggregation. Solid deposits of α-synuclein form in the brain, bringing with them a halo of toxic biochemistry that harms and kills neurons. It is expected that finding ways to clear these aggregates will prove to be an effective treatment for the condition, though there remain questions about the ordering of cause and effect. Does chronic inflammation or mitochondrial dysfunction lead to protein aggregation, or vice versa? As is usually the case, the easiest way to answer these questions is to clear the aggregates in a good disease model, or in the real thing in human patients, and see what happens.

Scientists have investigated the therapeutic potential of GM1 in Parkinson’s disease for nearly 30 years. Previous research showed that Parkinson’s patients have less GM1 than healthy patients in the part of the brain most affected by Parkinson’s, the substantia nigra. Other researchers followed this work to show in cell culture models that GM1 interacts with a protein called alpha-synuclein. In Parkinson’s disease, alpha-synuclein can form clumps, which can become toxic to brain cells in the substantia nigra and lead to cell death.

In new work, researchers have shown that giving daily GM1 doses to animals that overproduce alpha-synuclein inhibits the toxic effects of the protein. “When we looked in the brains of these animals, not only did we find we could partially protect their dopamine neurons from the toxic effects of alpha synuclein accumulation, we had some evidence that these animals had smaller and fewer aggregates of alpha-synuclein than animals that received saline injection instead of GM1.” In addition to protecting brain cells from death, the treatment also reversed some early motor symptoms.

The researchers suspect that less GM1 in the brains of Parkinson’s disease patients may facilitate the aggregation of alpha-synuclein and increase its toxicity. “By increasing GM1 levels in the brains of these patients, it would make sense that we could potentially provide a slowing of that pathological process and a slowing of the disease progression, which is what we found previously in a clinical trial of GM1 in Parkinson’s disease patients.” The team is now following up on their results to find out what other effects GM1 might have on alpha-synuclein.

Damage to Lymphatic Vessels Impairs Drainage of Cerebrospinal Fluid with Age

Impaired drainage of cerebrospinal fluid (CSF) with age is a hot topic in the field of neurodegeneration at the moment. In younger individuals, passage of CSF out of the brain via a number of routes is thought to provide a way to maintain normally low levels of metabolic waste, such as the amyloid-β associated with Alzheimer’s disease. Reduced fluid flow due to the damage and dysfunction of aging then contributes to the raised levels and aggregation of these waste products, and thus to neurodegenerative conditions. A number of companies are developing therapies based on this vision of brain aging, such as Leucadia Therapeutics. Thus we should expect to see impaired CSF drainage decisively proven or disproven as a major cause of neurodegeneration in clinical trials over the next few years. Even in advance of those trials, the evidence to date is quite compelling, however.

Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain’s cleansing mechanism. Scientists have now reported the basal side of the skull as the major route, so called “hotspot” for CSF drainage. They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain’s major drainage system, specifically basal mLVs are impaired with aging.

Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question – where is the main exit for the CSF? Though mLVs in the upper part of the skull were reported as the brain’s clearance pathways in 2014, no substantial drainage mechanism was observed in that section.

The researchers used several techniques to characterize the basal mLVs in detail and verified that specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs.

It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. By mapping out a precise route for the brain’s waste clearance system, this study may be able to help find ways to improve the brain’s cleansing function, enabling a new strategy for eliminating the buildup of aging-related toxic proteins.

Reversing Somatic Mosaicism in Aged Tissue

Somatic mosiacism is the tendency for aged tissues to display a mix of mutations, spread through cell lineages from an original mutation in a stem cell or progenitor cell. The consensus in the research community is that this degrades tissue function, contributing to the aging process, but there is a lack of evidence for whether or not this is significant across the present human life span. Clearly eventually it has to become a problem, given ways to deal with all of the other aspects of aging, but without a grasp of the size of the effect, it is hard to say whether or not this issue should be targeted now or later.

How does one go about repairing somatic mosiacism in any case? This is a tough question. Repairing diverse mutations in living tissue is possible in the grand scheme of things, given sufficiently advanced molecular nanotechnology, but it is possible with the tools of the next twenty years or so? That would likely mean programmable, highly efficient gene therapies, but in the open access paper here researchers demonstrate that, in the case of at least one gene, there may be other, simpler possibilities.

Normal tissues progressively accumulate cells carrying somatic mutations, some of which are linked to neoplasia and other diseases. This process is exemplified by human esophageal epithelium (EE), in which mutations generated by cell-intrinsic processes colonize the majority of normal epithelium by middle age. The most common mutations are under strong positive selection, meaning that there is an excess of protein altering over silent mutations within each gene. This indicates that these mutations confer a competitive advantage over wild-type cells and drive clonal expansions in normal tissue.

We speculated that, as in other systems of competitive selection, altering the tissue environment may change the relative fitness of particular mutations and their prevalence in the tissue. In this study, we focused on p53 mutations because these are the most enriched during malignant transformation. p53 is mutated in 5%-10% of normal EE but in almost all esophageal squamous cell carcinomas (ESCCs). This argues that ESCC emerges from the p53 mutant cell population in normal epithelium and that mutation of p53 is required for cancer development.

We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53-mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue.

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