Fight Aging! Newsletter, May 28th 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn’t work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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Contents

  • Cerebrospinal Fluid Flow Influences Neural Stem Cell Activity
  • Exercise Slows Aspects of Cardiovascular Aging, Protects Against Cell Stress
  • Intermittent Fasting Extends Life in Flies, But Not in the Expected Way
  • Vascular Risk and Amyloid Level in the Brain Interact to Speed Cognitive Decline
  • Does Malformed Lamin A Produce Enough Cellular Senescence to Contribute Meaningfully to the Progression of Aging?
  • Uncovering the Senolytic Mechanism of Piperlongumine
  • PCSK9, a Review of the Progress from Discovery to Therapy
  • A Fraction of Age-Related Frailty and its Consequences are Self-Inflicted
  • Reviewing the Development of Stem Cell Therapies for Osteoarthritis
  • Scaffolding Gel Spurs Regrowth of Damaged Brain Tissue
  • Escargot Gene Knockdown Extends Life in Flies
  • Reviewing Target Mechanisms for Exercise Mimetic Development
  • Are Mitochondria at the Root of Age-Related Loss of Muscle Mass and Strength?
  • Senescent T Cells as a Contributing Cause of Age-Related Autoimmunity
  • Progress Towards Ways to Make Old Stem Cells More Effective for Heart Repair

Cerebrospinal Fluid Flow Influences Neural Stem Cell Activity

https://www.fightaging.org/archives/2018/05/cerebrospinal-fluid-flow-influences-neural-stem-cell-activity/

Researchers have found that a physical mechanism in the brain, the flow of cerebrospinal fluid and the shear forces generated by that flow, influences the activity of neural stem cells via a distinctive set of biochemical signals. This will in turn influence the rate of neurogenesis, the creation of new neurons and their integration into existing neural networks. This process is important in learning, neurodegeneration, and the resilience of the brain when it comes to recovery from damage.

It is worth considering this recent discovery in the context of what is already known of reduced and impeded drainage of cerebrospinal fluid with age. The system of spaces through which cerebrospinal fluid circulates is not entirely closed off from the rest of the body, and normally drainage serves to remove metabolic wastes from the brain. It is thought that loss of drainage with age is an important contributing cause of the buildup of protein aggregates found in many neurodegenerative conditions, particularly the amyloid associated with Alzheimer’s disease.

More generally, the production of cerebrospinal fluid declines with age, its fluid pressure falls, and the flow characteristics both change and diminish. It is well known that neurogenesis rates also fall with aging, at least in the well explored mouse brain, and setting aside the present controversy over the existence of adult human neurogenesis. That the fluid dynamics of cerebrospinal fluid ties into this aspect of aging is perhaps an important advance in understanding, given that we are likely to see an increased focus on this part of the brain’s physiology from the Alzheimer’s research community in the years ahead.

Flow of cerebrospinal fluid regulates neural stem cell division

Researchers have discovered that the flow of cerebrospinal fluid is a key signal for neural stem cell renewal. Neural stem cells in the brain can divide and mature into neurons and this process plays important roles in various regions of the brain – including olfactory sense and memory. These cells are located in what is known as the neurogenic stem cell niche one of which is located at the walls of the lateral ventricles, where they are in contact with circulating cerebrospinal fluid.

The cerebrospinal fluid fills the brain and its roles are still poorly understood. This work highlights the role of this fluid as a key signal – but this time not a chemical but a physical signal. The mechanism is controlled by the ENaC molecule. This abbreviation stands for epithelial sodium (Na) channel and describes a channel protein on the cell surface through which sodium ions stream into the cell’s interior. “We were able to show in an experimental model that brain stem cells are no longer able to divide in the absence of ENaC. Conversely, a stronger ENaC function promotes cell proliferation.”

Further tests showed that the function of ENaC is augmented by shear forces exerted on the cells by the cerebrospinal fluid. The physical stimulation causes the channel protein to open for longer time and allow sodium ions to flow into the cell, thus stimulating division. “The results came as a big surprise, since ENaC had previously only been known for its functions in the kidneys and lungs.” Pharmacological ENaC blockers are already used clinically to relieve certain types of hypertension. Now it is known that they can also influence stem cells in the brain and thus brain function.

Epithelial Sodium Channel Regulates Adult Neural Stem Cell Proliferation in a Flow-Dependent Manner

One hallmark of adult neurogenesis is its adaptability to environmental influences. Here, we uncovered the epithelial sodium channel (ENaC) as a key regulator of adult neurogenesis as its deletion in neural stem cells (NSCs) and their progeny in the murine subependymal zone (SEZ) strongly impairs their proliferation and neurogenic output in the olfactory bulb.

Importantly, alteration of fluid flow promotes proliferation of SEZ cells in an ENaC-dependent manner, eliciting sodium and calcium signals that regulate proliferation via calcium-release-activated channels and phosphorylation of ERK. Flow-induced calcium signals are restricted to NSCs in contact with the ventricular fluid, thereby providing a highly specific mechanism to regulate NSC behavior at this special interface with the cerebrospinal fluid. Thus, ENaC plays a central role in regulating adult neurogenesis, and among multiple modes of ENaC function, flow-induced changes in sodium signals are critical for NSC biology.

Exercise Slows Aspects of Cardiovascular Aging, Protects Against Cell Stress

https://www.fightaging.org/archives/2018/05/exercise-slows-aspects-of-cardiovascular-aging-protects-against-cell-stress/

The glass half full view on exercise is that it modestly slows aging. The glass half empty view is that being sedentary accelerates age-related decline. Our species evolved in an environment that demanded considerably more physical activity than is the case in today’s era of comfort, calories, and machineries of transportation. Lacking that activity, we suffer. There are any number of papers that provide evidence showing that a surprisingly large fraction of cardiovascular and muscle aging, loss of function and loss of strength, is preventable. Exercise can’t stop aging, but it can certainly make a meaningful difference to quality of life along the way. If it was expensive, it might not be worth it. But it is free.

Today I’ll point out a couple of open access papers that cover aspects of the effects of exercise on function and cellular biochemistry in later life. They are representative of current views on the interaction between physical activity, metabolism, and the progression of aging. As is the case for calorie restriction, one of the interesting puzzles in the matter of exercise and health is how it can manage to be beneficial and yet have a comparatively small effect on life span in our species. Short-lived species have a much more intuitive response: interventions that improve their health tend to lengthen life expectancy to a proportionate degree. Not so in humans.

In fact, I would say that one of our defining features as a species, in comparison to smaller mammals, is just how little our lifestyle affects our life span, even while producing a sizable range in health status. So in mice, just the application of calorie restriction can extend life by 40%, while in humans the overall difference in life expectancy between a terrible lifestyle and an optimal lifestyle is, at best, 15% or so. The scientific understanding of the details of aging and cellular metabolism is not yet at the point that would allow us to do more than speculate as to how this can be the case, even as the short-term benefits of exercise and calorie restriction in mice and humans look very similar.

The effect of lifelong exercise frequency on arterial stiffness

Central arterial stiffness increases with sedentary aging. While near-daily, vigorous lifelong (more than 25 years) endurance exercise training prevents arterial stiffening with aging, this rigorous routine of exercise training over a lifetime is impractical for most individuals. The aim was to examine whether a less frequent ‘dose’ of lifelong exercise training (4-5 sessions per week for more than 30 minutes) that is consistent with current physical activity recommendations elicits similar benefits on central arterial stiffening with aging.

A cross-sectional examination of 102 seniors (60 years and older), who had a consistent lifelong exercise history was performed. Subjects were stratified into 4 groups based on exercise frequency as an index of exercise ‘dose’: sedentary: fewer than 2 sessions per week; casual exercisers: 2-3 sessions per week; committed exercisers: 4-5 sessions per week; Masters athletes: 6-7 sessions per week plus regular competitions. Detailed measures of arterial stiffness and left ventricular afterload were collected.

Biological aortic age and central pulse wave velocity were younger in committed exercisers and athletes compared to sedentary seniors. TACi (total arterial compliance) was lower, while carotid β-stiffness index and Eai (effective arterial elastance) were higher in sedentary seniors compared to the other groups. There appeared to be a dose-response threshold for carotid β-stiffness index and TACi. Peripheral arterial stiffness was not significantly different among the groups. This suggest that 4-5 weekly exercise sessions over a lifetime is associated with reduced central arterial stiffness in the elderly. A less frequent dose of lifelong exercise (2-3 sessions/wk) is associated with decreased ventricular afterload and peripheral resistance, while peripheral arterial stiffness is unaffected by any dose of exercise.

Long-Term Exercise Protects against Cellular Stresses in Aged Mice

Regular exercise improves the physical capacity and reduces the risk of developing chronic and age-related diseases by improving the metabolic state, antioxidant protection, and redox regulation. Lifelong training was reported to slow down aging-associated skeletal muscle fiber atrophy and prevent the reduction in muscular strength. Notably, acute intensive exercise induces the production of reactive oxygen species (ROS) that can evoke macromolecular damage, oxidative stress, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response (UPR).

On the other hand, regular exercise training results in adaptations in antioxidant defense and improves redox signaling to protect cells against stress-related diseases, thus delaying the aging processes. In addition, the UPR, which is activated by exercise in skeletal muscles, may exert protective effects against ER stress and can promote metabolic adaptation to physical activity. Long-term exercise was reported to upregulate heat shock protein (HSP) production in skeletal muscle, which would be beneficial in coping with oxidative stress, ER stress, and ER stress-related apoptosis. Nevertheless, the ability to induce HSPs in aged skeletal muscle is compromised, which may impair the exercise-mediated adaptation processes.

There is only limited information available on the association of aging and exercise training concerning oxidative stress, ER (SR) stress, UPR, and/or ER stress-related apoptosis in skeletal muscle. Our hypothesis is based on the fact that there is an age-induced disruption of redox regulation, increased redox ER stress, and ER stress-related apoptosis, and that long-term exercise can exert protective effects against these processes. We investigated the key molecular markers associated with redox state, ER stress, and apoptosis in skeletal muscle of old animals in a life-long running model and compared them to young animals. Our data demonstrated that aging induced oxidative stress and activated ER stress-related apoptosis signaling in skeletal muscle, whereas long-term wheel-running improved redox regulation, ER stress adaptation and attenuated ER stress-related apoptosis signaling. These findings suggest that life-long exercise can protect against age-related cellular stress.

Intermittent Fasting Extends Life in Flies, But Not in the Expected Way

https://www.fightaging.org/archives/2018/05/intermittent-fasting-extends-life-in-flies-but-not-in-the-expected-way/

The open access paper noted here is an example of present day intermittent fasting research, in flies in this case, in which researchers attempt to obtain a better understanding of how this dietary adjustment influences the pace of aging. The paper caught my eye for the examination of intestinal function. If you have been following the field in recent years, you may recall that the research community believes that intestinal function is central to the aging of flies, probably much more so than is the case in mammals. We can say that flies die from intestinal dysfunction in the same way we can say that humans die of cancer and heart disease – it is the dominant feature of decline and mortality in that species.

Intermittent fasting has been shown in a variety of species to have a broadly similarly effect to the more usual form of calorie restriction approaches, at least when the overall intake of calories is still restricted in comparison to a normal diet. However, it also extends life to some degree even when overall intake of calories is not restricted. Rodents on diets that have the same caloric intake but a different scheduling of that intake exhibit differences in the pace of aging. Time spent hungry appears important, in terms of triggering the nutrient-related stress responses that keep cells healthier and less damaged. This isn’t to say that the processes under the hood are identical: researchers have found considerable differences in gene expression between calorie restriction and intermittent fasting.

The time spent hungry hypothesis falters somewhat in the evidence from this study, not least because the background of historical evidence for intermittent fasting in flies is mixed. The evidence noted below suggests that intermittent fasting in flies, provided it is carried out in early life only, slows aging to benefit life span for reasons that are not the same as the usual nutrient-sensing mechanisms associated with calorie restriction. That is an interesting discovery. It may well be peculiar to flies due to the role of intestinal function in aging in those species, but I think that in general we should expect the effects of caloric intake to be more complex than simply a reflection of total calories over a period of time. That is probably true for any species.

Short-Term, Intermittent Fasting Induces Long-Lasting Gut Health and TOR-Independent Lifespan Extension

Intermittent fasting (IF), an umbrella term for diets that cycle between a period of fasting and non-fasting, has become increasingly popular as a weight loss regime (e.g., “every-other-day fasting” and the “5:2” diet). Advocates of IF argue that it shows many of the benefits seen with traditional daily energy restriction diets but with a simplified nutritional regime and increased compliance. Recent pilots and clinical trials used a fasting mimicking diet (FMD) (consisting of monthly cycles of a 5-day fast during which daily food intake was reduced to ∼50% normal caloric intake), which reduced multiple health risk factors during the post-fast recovery period, including lowered blood pressure, and reduced blood glucose and insulin-like growth factor-1 (IGF-1) levels. IF can extend lifespan in a variety of organisms, including bacteria, yeast, nematode worms, and mice. In animal models, IF has been shown to reduce the risk of developing a variety of age-related pathologies. IF is effective in preventing neurodegeneration in rodents and can attenuate cancer and cardiometabolic diseases, such as type II diabetes.

Reduced activity of nutrient-sensing pathways, with corresponding decrease in global protein translation, is implicated as an important mechanism underlying the pro-longevity effects of dietary interventions, such as dietary restriction (DR). Reduced TOR signaling is a hallmark of pro-longevity interventions, including DR, and treatment with the TOR inhibitor rapamycin extends healthy lifespan in a range of organisms. Although DR may exert some of its pro-longevity effects through reduced fecundity, DR can still extend lifespan in sterile Drosophila, implying that fecundity and lifespan can be uncoupled and that other mechanisms are also important.

Previous studies examining potential pro-longevity effects of IF in flies have produced mainly negative results. The first studies, almost 90 years ago, found that 6 hr of starvation in every 24 hr was beneficial and could extend lifespan. However, the effects of this IF regime may be strain or food medium specific, because a similar, more rigorous experiment ∼80 years later found that daily bouts of either 3 hr or 6 hr starvation throughout the adult life of the fly had neither a positive nor a negative effect on lifespan.

Here, we investigated a variety of IF regimes in flies and their effects on a range of health outcomes, including feeding behavior, gut and metabolic health, survival after stress, and lifespan. Importantly, short-term IF (the “2:5” diet) confined to early life robustly increased subsequent lifespan, particularly in females, independent of TOR signaling. Short-term IF also led to long-lasting health improvements, including increased stress resistance and a lower incidence of gut pathology that was associated with reduced bacterial abundance. Guts of flies 40 days post-IF showed a significant reduction in age-related pathologies and improved gut barrier function. We conclude that short-term IF during early life can induce long-lasting beneficial effects, with robust increase in lifespan in a TOR-independent manner, probably at least in part by preserving gut health.

Vascular Risk and Amyloid Level in the Brain Interact to Speed Cognitive Decline

https://www.fightaging.org/archives/2018/05/vascular-risk-and-amyloid-level-in-the-brain-interact-to-speed-cognitive-decline/

In a recent paper, researchers provided evidence to suggest that the risk factors associated with cardiovascular decline with age interact with amyloid-β in the brain to accelerate cognitive decline. Having more of both produces a worse prognosis, which is not all that surprising. This is the case in many areas of aging and age-related disease: forms of damage and dysfunction interact with one another, making consequences worse than would be the case if they were independent of one another. This is one of the reasons why aging is an accelerating process, starting off slow and picking up pace ever more rapidly as the damage and dysfunction mounts. It is also one of the reasons why it is hard to predict the benefit resulting from any given approach to rejuvenation based on damage repair without actually trying it.

Cardiovascular risk factors such as raised blood pressure and excess fat tissue somewhat measure and somewhat predict the pace at which the complex machinery of blood vessels ages. In particular the failure of smooth muscle in blood vessel walls to correctly react to circumstances with dilation and contraction, the loss of capillaries delivering nutrients to energy-hungry tissues like the brain, and the progression of atherosclerosis, weakening and narrowing blood vessels with fatty plaques. There are other important processes, however, such as the routes for drainage of cerebrospinal fluid, or other ways in which amyloid-β and other metabolic waste might exit the brain.

Past research has shown that there is an equilibrium of sorts between amyloid-β in the brain and amyloid-β in the vascular system outside the brain. It is possible to drain amyloid-β from the brain to some degree by reducing it elsewhere in the body, indicating that there are processes transporting amyloid-β into the blood system, in addition to those removing it via other paths of cerebrospinal fluid drainage. This likely involves the blood-brain barrier, a part of blood vessel walls where they pass through the central nervous system, and thus is impacted by the state of vascular aging and dysfunction. This is the sort of thing one would look into if searching for the mechanisms underlying the relationship noted in the research below.

Vascular risk factors interact with amyloid-beta levels to increase age-related cognitive decline

Alzheimer’s disease and cerebrovascular disease are probably the two most common causes of cognitive impairment in the elderly, but even though they often co-occur in individual patients, they are typically viewed as independent contributors. While the presence of amyloid plaques in the brain is considered a hallmark of Alzheimer’s disease, some individuals with elevated amyloid levels never develop cognitive impairment. This has led to a search for additional markers beyond brain amyloid to help identify those at increased risk for cognitive decline.

The current study was designed to investigate whether the effects of increased brain amyloid and of vascular risk on cognitive decline are merely additive, reflecting a simple combination of the risks independently contributed by each factor, or synergistic, in which interaction of the two produces an even higher level of risk. The study analyzed data from 223 participants in the Harvard Aging Brain Study, an ongoing study of cognitively normal individuals ages 50 to 90 designed to improve understanding of brain changes affecting memory and cognition that occur with aging.

Upon enrollment in the study, participants receive standard imaging biomarker studies, including PET scans with a compound that reveals amyloid deposits in the brain. Assessment of vascular risk is determined by the Framingham cardiovascular risk score, which is based on factors such as hypertension, body mass index, and histories of diabetes or smoking. Participants also receive standard tests of memory, attention and language, which are repeated at annual follow-up visits.

The results showed that both elevated brain amyloid levels and higher vascular risk, as measured upon study enrollment, were associated with more rapid cognitive decline, with the most rapid changes seen in participants with elevations in both factors. The extent of the interaction between the two measures suggested a synergistic, rather than simply an additive effect.

Vascular risk factors interact with amyloid-beta levels to increase age-related cognitive decline

Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease (AD) is crucial to the success of clinical trials aimed at preventing dementia. The advent of in vivo measures of β-amyloid (Aβ) burden highlighted a preclinical phase of AD allowing for the identification of clinically normal individuals with objective evidence of AD pathology. However, a substantial portion of individuals who are amyloid positive do not show clear evidence of cognitive decline in available longitudinal follow-up data. This is consistent with autopsy data indicating that approximately 30% of clinically normal elderly individuals have signs of elevated Aβ burden on pathological examination. These findings have prompted the search for additional biomarkers that can be used with Aβ burden to identify individuals at maximal risk of cognitive decline.

Multiple studies have demonstrated that cardiovascular risk factors, such as hypertension and hyperlipidemia (which often occur together), are also risk factors for cognitive decline and AD. Consistent with this, recent epidemiological data suggest that declining dementia incidence may be partially because of advances in the treatment of cardiovascular disease. Neuropathological studies indicate that vascular brain changes frequently co-occur with AD pathology in late-onset dementia and that vascular pathology may lower the threshold for cognitive impairment.

The goal of the present study was to examine whether a well-validated, multivariable measure of vascular risk is associated with prospective cognitive decline in a large cohort of clinically normal elderly individuals, either additively or synergistically with Aβ burden.

Does Malformed Lamin A Produce Enough Cellular Senescence to Contribute Meaningfully to the Progression of Aging?

https://www.fightaging.org/archives/2018/05/does-malformed-lamin-a-produce-enough-cellular-senescence-to-contribute-meaningfully-to-the-progression-of-aging/

Progeria is one of the better known accelerated aging conditions. It isn’t actually accelerated aging, but rather one specific runaway form of cell damage that gives rise to general dysfunction in cells throughout the body. Since degenerative aging is also a matter of general dysfunction in cells throughout the body, there is some overlap in the observed results, even though the root causes are completely different. So progeria patients appear, superficially at least, to be prematurely aged, and die from heart disease early in life.

The cause of progeria was discovered to be a mutation in the Lamin A (LMNA) gene, resulting in a malformed protein now called progerin. This protein is an important structural component of the cell nucleus. If it doesn’t function correctly, the nucleus becomes misshapen, and near all processes involving nuclear DNA maintenance and gene expression – the production of needed proteins at the right time from their genetic blueprints – cease to work correctly. The cell becomes dysfunctional. When near all cells are in this state, the prognosis for the individual is dire. Interestingly, in the years since this discovery, it has become clear that progerin is also present in small amounts in genetically normal older individuals. There is some debate over whether or not this is important in the progression of aging. Does it cause enough damage, or is it insignificant in comparison to other harmful processes?

In this context, we can consider cellular senescence, a mechanism closely connected to DNA damage, by which a small number of problem cells can cause outsized amounts of harm. Another possibility is damage to stem cells, as they are also small in number but highly influential on tissue function. Cells become senescent in response to internal damage, including that produced by progerin, and then either self-destruct or linger to secrete a potent mix of inflammatory and other signals. It is these signals, the senescence-associated secretory phenotype, that allows a comparatively small number of cells to produce comparatively large problems. It is known that senescent cells are important in many age-related conditions, particular those with a strong inflammatory component. Is generation of progerin significant as a cause of cellular senescence in normal aging, however? In this open access paper, researchers consider some of the mechanisms involved.

GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A-mediated human mesenchymal stem cell aging

The LMNA gene encodes lamin and lamin C, which are major components of the nuclear lamina. Mutations in the LMNA gene have been implicated in premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). HGPS is caused by splicing defect and consequent generation of progerin, mutant-truncated lamin protein. Cells of HGPS patients exhibit an abnormal nuclear structure, increased DNA damage and premature senescence. In addition to the effects of progerin, accumulation of prelamin A, precursor of lamin A, induces defects in nuclear structures. ZMPSTE24 is an enzyme that produces mature lamin by cleavage of amino acids in prelamin A.

Zmpste24 knock-out mice have been widely used to study the mechanisms of aging and progeria. Depletion of Zmpste24 causes premature senescence in mice, including decreases in life span and bone density. Increased prelamin expression caused by ZMPSTE24 deficiency causes defective DNA repair. Zmpste24 knock-out mice have been extensively studied because of their impaired DNA damage response (DDR). Lamin also functions as a structural barrier to DDR. Altogether, these findings indicate that defects in the nuclear structure induced by progerin or prelamin lead to the accumulation of DNA damage, which results in accelerated aging.

It has been reported that exogenous expression of progerin in human mesenchymal stem cells (hMSCs) can impair their differentiation potential. Furthermore, production of induced pluripotent stem cells (iPSCs) from HGPS patients has revealed that the progerin expression levels are the highest in MSCs, vascular smooth muscle cells, and fibroblasts. These results indicate that MSCs are a specific target cell type of progerin-induced senescence. Like progerin, excessive accumulation of prelamin induces premature senescence in MSCs, including wrinkled nuclei. Downregulation of ZMPSTE24 in hMSCs also induces the senescence phenotype. These investigations imply that both progerin and prelamin can induce senescence in hMSCs with change in nuclear morphology.

Senescent cells secrete a group of factors that induce senescence in neighboring cells, a phenomenon termed senescence-associated secretory phenotype (SASP). The secreted inflammatory factors propagate senescence and recruit immune cells to senescent tissues by the generation of a pro-inflammatory environment. Among the factors reported to regulate the SASP, GATA4 has been recently identified as a regulator of senescence and inflammation. GATA4 is expressed during oncogene- and irradiation-induced senescence in fibroblasts in response to DNA damage. During the process of cellular senescence, GATA4 has a regulatory role in the SASP of fibroblasts. Because GATA4-dependent cellular senescence is closely associated with DDR, the role of GATA4 in other senescence models and other cell types may reveal a new mechanism.

Senescent hMSCs also induce senescence in neighboring cells. Monocyte chemoattractant protein-1 (MCP-1) secreted from senescent human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) induces premature senescence in neighboring cells. Insulin-like growth factor binding proteins are also produced by senescent hMSCs, and they trigger senescence in adjacent normal cells. These studies investigated the mechanisms of the SASP by inducing senescence in hMSCs through prolonged passaging. However, cellular senescence of MSCs can be regulated by various factors other than passaging. In our previous report, we have demonstrated that depletion of ZMPSTE24 and introduction of progerin induce premature senescence in hUCB-MSCs. It remains to be determined whether defective lamin triggers paracrine senescence via inflammatory factors in hMSCs.

In this study, we identified that paracrine senescence is triggered in senescent hMSCs with abnormal nuclear structures by increasing the expression of MCP-1 and that inhibition of MCP-1 decreases the SASP. Furthermore, we found that GATA4 mediates the senescence of hMSCs induced by defective lamin A. We assessed whether down-regulation of GATA4 disturbs the progerin- or prelamin A-dependent senescence phenotype. Elucidating how GATA4 regulates senescence in hMSCs with nuclear defects may aid in understanding the etiology of complex aging disorders. We show that inhibition of GATA4 expression protects hMSCs from cellular senescence, implying unique therapeutic opportunity against progeroid syndromes and physiological aging.

Uncovering the Senolytic Mechanism of Piperlongumine

https://www.fightaging.org/archives/2018/05/uncovering-the-senolytic-mechanism-of-piperlongumine/

Senolytic compounds are those capable of selectively destroying senescent cells. They are useful because the buildup of senescent cells over time is one of the root causes of aging. A number of mechanisms have been discovered by which senescent cells can be provoked into self-destruction, such as bcl-2 inhibition or interference in FOXO4-p53 interactions. These examples are fairly well understood. Other mechanisms are known but less well understood; they require more work in order to proceed on the production of improved senolytic compounds.

In some cases, however, the primary mechanism of action of a compound found to be senolytic through experimental screening isn’t yet known. The open access paper noted here is an example of how to move forward in this situation: the researchers report on their efforts to characterize the mechanism underlying the ability of piperlongumine to selectively destroy senescent cells. This line of work has been ongoing for a few years now; it takes time. Given sufficiently knowledge of the mechanism, however, it is usually possible to find or develop more effective candidate drugs in this family. Piperlongumine isn’t perfect, and can be improved upon.

Cellular senescence occurs when irreversible cell cycle arrest is triggered by telomere shortening or exposure to stress. Senescent cells (SCs) accumulate if they cannot be removed rapidly by the immune system due to immune dysfunction and/or a sustained, overwhelming increase in SC production. This occurs during aging or under certain pathological conditions. Under these circumstances, SCs can be detrimental and play a causal role in aging, age-related diseases, and chemotherapy- and radiotherapy-induced side effects, in part through the expression of the senescence-associated secretory phenotype.

This hypothesis is supported by recent studies demonstrating that the genetic clearance of SCs prolongs the lifespan of mice and delays the onset of several age-related diseases and disorders in both progeroid and naturally aged mice. Therefore, the pharmacological clearance of SCs with a small molecule, a senolytic agent that can selectively kill SCs, is potentially a novel anti-aging strategy and a new treatment for chemotherapy- and radiotherapy-induced side effects.

However, a major challenge facing the discovery and development of effective senolytic agents is to identify and validate more senolytic targets. Since the first senolytic was published, twelve molecular targets have been identified. These findings led to the discovery of a few senolytic agents, but the clinical application of these senolytic agents for age-related diseases and cytotoxic cancer therapy-induced side effects may be limited by agent toxicity and manufacturing challenges.

Piperlongumine (PL) is one of a few natural products identified to have the ability to selectively kill SCs. Compared to other known senolytic agents, PL has the advantage of low toxicity, an excellent PK/PD profile, and oral bioavailability. However, its molecular targets and mechanisms of action are unknown. To facilitate the development of PL and its analogues as senolytic drug candidates, it is critical to identify PL molecular targets, which can form a molecular basis for the rational design of new PL analogues.

Herein, we report the identification and validation of oxidation resistance 1 (OXR1) as a molecular target of PL in SCs. OXR1 is a cellular oxidative stress sensor that regulates the expression of a variety of antioxidant enzymes and modulates the cell cycle and apoptosis. We found that OXR1 was upregulated in SCs induced by ionizing radiation or extensive replication. PL bound to OXR1 directly and induced its degradation through the ubiquitin-proteasome system in an SC-specific manner. Knocking down OXR1 selectively induced apoptosis in SCs and sensitized the cells to oxidative stress caused by hydrogen peroxide (H2O2). These findings suggest that OXR1 is a potential senolytic target that can be exploited for the development of selective senolytic agents with improved potency and selectivity. In addition, these findings also provide new insight into the mechanism by which SCs are highly resistant to oxidative stress.

PCSK9, a Review of the Progress from Discovery to Therapy

https://www.fightaging.org/archives/2018/05/pcsk9-a-review-of-the-progress-from-discovery-to-therapy/

PCSK9 inhibition therapies dramatically reduce cholesterol levels in the bloodstream, and seem set to take over from statins as the next generation approach to cholesterol management in the context of cardiovascular disease risk. Atherosclerosis results from the ability of a combination of damaged lipids – such as oxidized cholesterol – and overall level of lipids to overwhelm macrophage cells called in to clean up points of irritation in blood vessel walls. A feedback loop of inflammation and cell death sets in, as macrophages, filled with lipids and in the process of dying, call for further help, secreting cytokines that produce inflammation. The fatty deposits that weaken and narrow blood vessels in the later stages of atherosclerosis are composed of dead macrophages and the lipids they failed to clean up.

One way to try to slow down this runaway process of damage is to reduce the input of cholesterol. This is the basis of the success of statins in lowering cardiovascular risk, and the evidence suggests that further lowering of cholesterol levels will reduce that risk to a greater degree. This is still, however, only a stepping stone on the way to an effective and complete solution. PCSK9 inhibition doesn’t halt or significantly reverse atherosclerosis, it still only slows it down somewhat. The research community must focus on different mechanisms and strategies, such as perhaps ways to make macrophages more resilient and more effective, allowing them to continue to operate in old people just as well as they do in young people. The SENS approach of removing oxidized lipids via delivery of bacterial enzymes is one example.

Unknown 15 years ago, PCSK9 (proprotein convertase subtilisin/kexin type 9) is now common parlance among scientists and clinicians interested in prevention and treatment of atherosclerotic cardiovascular disease. What makes this story so special is not its recent discovery nor the fact that it uncovered previously unknown biology but rather that these important scientific insights have been translated into an effective medical therapy in record time. Indeed, the translation of this discovery to novel therapeutic serves as one of the best examples of how genetic insights can be leveraged into intelligent target drug discovery.

Initial clues were provided by a French family with familial hypercholesterolemia (FH) in 2003. Gain-of-function mutations in PCSK9 were linked with hypercholesterolemia and ultimately uncovered a key new player in lipid metabolism. This seminal discovery led to a series of investigations that demonstrated that loss-of-function (LOF) mutations in PCSK9 associate with lifelong low cholesterol levels and marked reductions in the risk of atherosclerotic cardiovascular disease (ASCVD). The rare individuals with homozygous LOF mutations in PCSK9 (and no circulating protein) demonstrated extremely LDL cholesterol (LDL-C; ≈15 mg/dL), normal health and reproductive capacity, and no evidence of neurological or cognitive dysfunction.

This complementary set of observations has been leveraged into the most important therapy for the treatment of hypercholesterolemia and ASCVD since the introduction of statins. Indeed, the so-called PCSK9 inhibitors, fully human monoclonal antibodies that bind PCSK9, reduce LDL-C by ≈60% and risk of myocardial infarction and stroke by ≈20% after more than 2 years of treatment. Remarkably, these agents antagonizing PCSK9 action were approved by regulatory agencies spanning the globe only a decade after its discovery – although the scientific and medical communities have swiftly uncovered many facets of PCSK9 biology, there is still much to learn.

A Fraction of Age-Related Frailty and its Consequences are Self-Inflicted

https://www.fightaging.org/archives/2018/05/a-fraction-of-age-related-frailty-and-its-consequences-are-self-inflicted/

While regular moderate exercise appears to have only modest effects on overall longevity – five years or so at most, based on the epidemiological data – it does greatly improve long term health. The same might be said of avoiding weight gain, and thereby the consequences of excess visceral fat tissue. Studies suggest that some fraction of the decline of aging is self-inflicted, in the sense of being due to a lack of suitable exercise, gain of weight, smoking, and the like. While it isn’t possible to avoid growing old, more of the unpleasant portions of aging can be evaded than is thought to be the case by the public at large. Being sedentary has real consequences when it comes to health and quality of life in later years.

New research has shown that older people with very low heart disease risks also have very little frailty, raising the possibility that frailty could be prevented. The largest study of its kind found that even small reductions in risk factors helped to reduce frailty, as well as dementia, chronic pain, and other disabling conditions of old age. Many perceive frailty to be an inevitable consequence of ageing – but the study found that severe frailty was 85% less likely in those with near ideal cardiovascular risk factors.

“This study indicates that frailty and other age-related diseases could be prevented and significantly reduced in older adults. Getting our heart risk factors under control could lead to much healthier old ages. Unfortunately, the current obesity epidemic is moving the older population in the wrong direction, however our study underlines how even small reductions in risk are worthwhile.” The study analysed data from more than 421,000 people aged 60-69 in both GP medical records and in the UK Biobank research study. Participants were followed up over ten years.

The researchers analysed six factors that could impact on heart health. They looked at uncontrolled high blood pressure, cholesterol and glucose levels, plus being overweight, doing little physical activity and being a current smoker. “Individuals with untreated cardiovascular disease or other common chronic diseases appear to age faster and with more frailty. In the past, we viewed ageing and these common chronic diseases as being both inevitable and unrelated to each other. Now our growing body of scientific evidence on ageing shows what we have previously considered as inevitable might be prevented or delayed through earlier and better recognition and treatment of cardiac disease.”

Reviewing the Development of Stem Cell Therapies for Osteoarthritis

https://www.fightaging.org/archives/2018/05/reviewing-the-development-of-stem-cell-therapies-for-osteoarthritis/

Arguably, age-related joint issues are where comparatively simple, first generation stem cell therapies have so far had their greatest and most reliable impact. To pick one example, mesenchymal stem cell therapies effectively reduce chronic inflammation for an extended period of time, achieving this result via the signals secreted by the transplanted stem cells in the comparatively short time they remain alive in the patient. Since arthritis is an inflammatory condition, and given that chronic inflammation interferes in the processes of healing, a reduction may spur some degree of increased tissue maintenance activity and repair. Reports suggest that this consequent regeneration is a lot less reliable than the reduction of inflammation, however.

Osteoarthritis (OA) is a prevalent debilitating joint disorder characterized by erosion of articular cartilage. The degradation of network of collagen and proteoglycan in OA cartilage leads to a loss in tensile strength and shear properties of cartilage. Interestingly, though OA manifests as loss of the articular cartilage, it also includes all tissues of the joint, particularly the subchondral bone. Besides aging, the increase in level of accumulation of advanced glycation end products (AGEs), oxidative stress, and senescence-related secretory phenotypes are a few reported factors associated with pathogenesis of OA.

The potential of stem cells to differentiate into osteoblasts, chondroblasts, and adipocytes, if stimulated properly, can regenerate cartilage both in vivo and in vitro. Recent progress in tissue engineering has highlighted the regenerative potential of stem cells for therapeutic purposes. The multilineage potential of stem cells, suitable scaffolds, and appropriate chondrogenic agent (chemical and mechanical stimuli) have been implicated to regenerate damaged cartilage. Mesenchymal stem cell (MSC) based therapy is also emerging as alternative to joint replacement with prostheses, due to its long-lasting effect.

MSCs derived from bone marrow (BMSCs) are capable enough to differentiate into tissues such as bone and cartilage and mobilize at an injured cartilage site in knee joints thereby assisting in cartilage regeneration in OA. In a study, the intra-articularly transplanted BMSC successfully regenerated injured cartilage in an animal model of OA and also improved osteoarthritic symptoms in humans without any major side effect even in the long-term. This study demonstrated the possibility of intra-articular injection of MSCs for the treatment of injured articular tissue including anterior cruciate ligament, meniscus, or cartilage. Therefore, if this treatment option is well-established, it may be minimally invasive procedure compared to conventional surgeries.

Scaffolding Gel Spurs Regrowth of Damaged Brain Tissue

https://www.fightaging.org/archives/2018/05/scaffolding-gel-spurs-regrowth-of-damaged-brain-tissue/

Scaffold materials are widely used in regenerative research. They often take the form of gels, making it possible to inject and shape the scaffold in damaged internal tissue. These nanoscaled materials are mixed in with signal molecules that spur cell growth. The scaffold both supports cells structurally and encourages them to correctly rebuild natural tissue, complete with its extracellular matrix. The scaffold itself is degraded by cells and replaced by that tissue – at least in the ideal circumstance.

This has been demonstrated in a variety of tissues, particularly muscle, but here researchers have managed a much more challenging feat by convincing the brain to regenerate. It remains to be seen how well this restores lost function; that is much harder to evaluate in animals than the evident fact of structural repair. Nonetheless, this seems an important development. If the central nervous system can be induced to repair itself effectively, that will open a great many doors presently closed in the extension of human life.

In a first-of-its-kind finding, a new stroke-healing gel helped regrow neurons and blood vessels in mice with stroke-damaged brains. The results suggest that such an approach may someday be a new therapy for stroke in people. The brain has a limited capacity for recovery after stroke and other diseases. Unlike some other organs in the body, such as the liver or skin, the brain does not regenerate new connections, blood vessels, or new tissue structures. Tissue that dies in the brain from stroke is absorbed, leaving a cavity, devoid of blood vessels, neurons, or axons, the thin nerve fibers that project from neurons.

To see if healthy tissue surrounding the cavity could be coaxed into healing the stroke injury, researchers engineered a gel to inject into the stroke cavity that thickens to mimic the properties of brain tissue, creating a scaffolding for new growth. The gel is infused with molecules that stimulate blood vessel growth and suppress inflammation, since inflammation results in scars and impedes regrowth of functional tissue.

After 16 weeks, stroke cavities in treated mice contained regenerated brain tissue, including new neural networks – a result that had not been seen before. The mice with new neurons showed improved motor behavior, though the exact mechanism wasn’t clear. “The new axons could actually be working. Or the new tissue could be improving the performance of the surrounding, unharmed brain tissue.” The gel was eventually absorbed by the body, leaving behind only new tissue.

Escargot Gene Knockdown Extends Life in Flies

https://www.fightaging.org/archives/2018/05/escargot-gene-knockdown-extends-life-in-flies/

Escargot (esg) is a gene in the Snail family of genes in fruit flies. After a certain point, it doesn’t really help all that much to peer too closely at the nomenclature of genes – it is best to just accept it and move on. Reduced levels of esg modestly extend life in flies, as researchers here demonstrate. As to why this is the case, here as in so many other cases, understanding is lacking. There are a few core mechanisms of plasticity in aging, linking the operation of cellular metabolism to natural variations in longevity between individuals. These largely relate to the activation of stress responses due to environmental circumstances, such as a lack of nutrients, but an enormous number of genes and proteins can influence those core mechanisms. The map of cellular biochemistry is far from complete in all of its details, and thus sometimes all that can be done is to look at relationships and speculate.

The nervous system is a key player in maintaining homeostasis and the structural and functional integrity of living beings and, hence, in controlling aging and longevity. Given the role of the nervous system in life span control, a reasonable question would be whether genes defining the cellular specificity of neurons are also involved, in some way, in the regulation of longevity.

We have already demonstrated that several genes that encode RNA polymerase II transcription factors and that are involved in neural development affect life span in Drosophila melanogaster. Among other genes, escargot (esg) was identified as a candidate gene affecting life span in a screen of more than 1,500 insertion mutations and the insertion located downstream of esg was further confirmed to be causally associated with life span control.

The gene esg belongs to the Snail family of genes that are involved in the development of the nervous system in arthropods and chordates. In Drosophila melanogaster, Esg and other Snail proteins act to control asymmetric neuroblast division during embryogenesis; however, Esg functions are not exclusively neuronal, and it also participates in the maintenance of intestinal and male germ cells, regulates tracheal morphogenesis and development of the genital disk, and determines wing cell fate.

Here, we present new data on the role of esg in life span control. Analysis of the esg-BG01042 mutation allowed us to show that esg is involved in the regulation of life span, to varying degrees, in unmated and mated males and females. The esg-BG01042 mutation also increased locomotion, specifically during old age, indicating that the mutation slowed down aging. The increase in longevity was caused by decreased esg transcription associated with structural changes in the DNA sequences downstream of the gene.

Targets of esg encoded enzymes involved in the biosynthesis of neurotransmitters, neuropeptides, cationic transporters, and other proteins. Among others, genes involved in the defense/immune response were both up- and down-regulated. Of the genes known to be involved in life span control, at least two genes associated with increased life span, heat shock protein 26 (hsp26) and NAD-dependent methylenetetrahydrofolate dehydrogenase (Nmdmc), increased transcription.

Reviewing Target Mechanisms for Exercise Mimetic Development

https://www.fightaging.org/archives/2018/05/reviewing-target-mechanisms-for-exercise-mimetic-development/

The open access paper noted here reviews some of the known molecular targets for the development of exercise mimetics. An exercise mimetic is a therapy that in some way triggers a fraction of the beneficial cellular response to exercise. Exercise mimetic development lags behind calorie restriction mimetic development, and both are very slow, very expensive lines of work with – so far – little to show in terms of practical, useful therapies. It remains the case that it is far easier and better to actually exercise or practice calorie restriction. Even when the first truly effective therapies are available in the clinic, and it must be said there is no real sign that this will happen before the late 2020s, they are unlikely to be as beneficial as either exercise or calorie restriction. The cellular response to stress is very complex and includes many distinct mechanisms; efforts to produce mimetic drugs tend to focus down on only a fraction of those mechanisms.

Exercise benefits young and old organisms, including increased skeletal mass, improvement in the cardiovascular system, and metabolic regulation, as well as in brain functions associated with cognition, memory, and mood. In particular, exercise promotes adult hippocampal neurogenesis and neuronal plasticity, and is associated with increased memory performance and cognition, and is considered to counter cognitive decline caused by aging and by neurodegenerative diseases.

Skeletal muscle is the most abundant tissue in the human body and the most highly activated organ in response to physical activity. Aerobic exercise affects skeletal muscle by inducing a substantial switch in composition from fast-twitching, glycolytic type IIb fibers to the more oxidative, slow-twitching type I fibers. Endurance training results in an increase in mitochondrial biogenesis and activity, vascularization, oxygen consumption and an overall improvement of aerobic capacity. Furthermore, the resulting activation of signaling pathways relevant to energy metabolism, such as the AMPK-SIRT1-PGC-1α pathway in muscle may contribute to the benefits of exercise for brain function.

The vast beneficial consequences of exercise might not be within reach of debilitated, diseased, and elderly patients. The development of compounds capable of activating cellular targets of exercise may be a new therapeutic approach. Indeed, recent research indicates that factors secreted by skeletal muscle during exercise may exert beneficial effects on brain function. This review will focus on the identified targets relevant to energy metabolism in muscle and the molecules affecting it.

An active lifestyle, despite the promising of compounds currently under study, remains the preferred choice for improving body and brain function. Indeed, the mechanisms of action of exercise mimetics still require further investigation, and the possibility of a treatment capable of replacing exercise in its entirety is remote. In order to achieve an artificial exercise regimen, potential adverse effects of prolonged treatment with exercise mimetics have to be overcome. Nonetheless, a possible use of this class of compounds could be envisioned in parallel with light training paradigms, helping to achieve a more complete exercise-induced benefit, both on brain and on peripheral functions. This is especially poignant for conditions, such as morbid obesity or neurodegenerative diseases, which may preclude exercise.

Are Mitochondria at the Root of Age-Related Loss of Muscle Mass and Strength?

https://www.fightaging.org/archives/2018/05/are-mitochondria-at-the-root-of-age-related-loss-of-muscle-mass-and-strength/

Sarcopenia, the age-related loss of muscle mass and strength, has many possible contributing causes. There is fair evidence for most of them, from a failure to process amino acids needed for construction of new muscle mass to damaged neuromuscular junctions to loss of stem cell function. The most compelling evidence I’ve seem points to that stem cell dysfunction as the most significant contribution. It is certainly the case that stem cell populations decline in size and activity with age, reducing the supply of daughter cells needed to maintain tissues in good condition. Muscle stem cells are among the most studied in aging research.

The paper noted here picks through the major themes in sarcopenia, and makes the argument for linking at least some of them to age-related issues in mitochondrial function. The mitochondria are the power plants of the cell, and muscle is an energy-hungry tissue. Mitochondria can suffer forms of damage that make them harmful to their cells and the surrounding tissue; this is a significant issue in aging. More generally, all mitochondria change for the worse in old tissues, possibly in reaction to other forms of molecular damage characteristic to old tissues. They alter in shape and dynamics, and their ability to generate the energy store molecules required for cellular operations declines. How much of sarcopenia can be explained by these phenomena? Some, I think, possibly not all.

Using a targeted metabolomics approach, participants with low muscle quality presented significantly higher plasma concentrations of isoleucine and leucine, suggesting that low muscle quality is characterized by impaired transport of amino acids, especially branched chain amino acids (BCAAs), across the muscle cell membrane. The exact reasons for why amino acid uptake is reduced in older persons with low muscle quality are unknown, and further work is required to identify putative intervention/therapeutic targets.

Physiologically, amino acid uptake in muscle cells is regulated by three fundamental mechanisms: insulin signalling, BCAA (primarily leucine) blood concentration, and physical activity. Previous studies have also suggested that these ‘anabolic’ signals cause increased amino acid entry by dynamically enhancing muscle perfusion, and all three signals exhibit a dose-response relationship that is steeper in younger than in older persons. In other words, older persons tend to develop an ‘anabolic resistance’ to the three stimuli. Since muscle perfusion adaptation is mediated by endothelial reactivity, which is hampered by a pro-inflammatory state, this hypothesis can also explain why inflammation is such a strong correlate and predictor of age-related sarcopenia.

During ageing, mitochondria lose the ability to produce energy during maximal efforts but not when the energetic demand is lower. This impaired mitochondrial function could be due to inadequate perfusion or reduced muscle blood flow, resulting in lower oxygen delivery in skeletal muscle and diminished aerobic capacity. This hypothesis is interesting because it connects both energetic and anabolic deficits to the same mechanism. These results indicate that oxidative phosphorylation is progressively impaired with ageing; it is unclear whether this is because the number of mitochondria per muscle volume is diminished, the intrinsic capacity of mitochondria to generate ATP is impaired, or the availability of oxygen and nutrients at different levels of effort is compromised.

Oxidative stress and defective mitophagy (mitochondrial autophagy) are potentially involved in the decline of muscle quality with ageing and need to be considered. Dysfunctional mitochondria are characterized by reduced oxidative phosphorylation efficiency and excessive production of reactive oxygen species, which oxidize and damage macromolecules. The hypothesis that oxidative stress causes degenerative changes in tissues that are highly metabolically active, such as the brain and the muscle, has been proposed for many years. Oxidative stress may also affect satellite cells or muscle stem cell pools in skeletal muscle.

Defective mitochondrial function has been studied in regard to the neuromuscular junction (NMJ) remodelling that occurs with ageing, producing cycles of denervation-innervation that lead to motor unit loss, specifically in type II fibres, as well as muscle fibre atrophy. However, it is not clear whether these changes in the NMJ precede or follow the observed decline in muscle mass and strength that is observed with ageing. Some studies have reported altered mitochondria morphology in the NMJ that produce increased levels of oxidative stress, decreased enzymatic activity and ATP production, and impaired calcium buffering. The combination of these biological changes may have a strong negative impact on excitation-contraction coupling and eventually lead to the loss of motor units.

Overall, low muscle quality seems to be associated with (i) metabolic impairments that lead to reduced incorporation of the three major BCAAs, which are used by muscle as energy sources and are associated with muscle strength and endurance; (ii) fat accumulation in muscle tissue that ultimately leads to architectural disruption and loss of function; and (iii) high concentration of lipid species that are associated with impaired mitochondrial function and unrecycled mitochondrial proteins, potentially due to defective mitophagy or proteostasis. The extent and complexity to which these mechanisms are interconnected is unknown and should be examined in future studies. In addition, other factors that impact ageing muscle could also modulate mitochondrial function, such as (i) defects in the NMJ that leads to myofiber denervation-due to reduced capacity in motor neurons to reinnervate muscle fibres-consequently causing fibres to become atrophied; (ii) the age-associated decline in the satellite cell pool, reducing muscle regeneration after injury; and (iii) ‘inflammaging’, the chronic low-grade inflammation observed in older persons.

Senescent T Cells as a Contributing Cause of Age-Related Autoimmunity

https://www.fightaging.org/archives/2018/05/senescent-t-cells-as-a-contributing-cause-of-age-related-autoimmunity/

The more familiar autoimmune conditions, such as rheumatoid arthritis, are not all that age-related. Like cancer in young adults, they are a rare and unlucky happenstance, a form of most likely random cellular malfunction that spreads far enough to cause major problems. In later life, however, there occur a wide range of less familiar, less categorized, and comparatively poorly understood autoimmune conditions. It is an area of active research and many unknowns – look at just how recently type 4 diabetes was identified, for example.

These age-related autoimmunities arise from the chaotic failure of the immune system in late life. Cells fall into a variety of unhealthy states, malfunctioning cells dominate over useful cells, the immune system as a whole flails, producing chronic inflammation while failing at its primary tasks, and the supply of new competent immune cells diminishes dramatically. The publication here considers just one type of problem immune cell, those that have become senescent. This, fortunately, is an area in which solutions lie just around the corner. There is every reason to believe that senescent immune cells will be just as vulnerable to destruction by senolytic therapies as any other kind of senescent cell. If they are destroyed, they will cause no further harm, and the patient will be in a better position.

Immune aging (immunosenescence) is characterized by the reduced competence of acquired immunity, leading to increased susceptibility to infection as well as decreased vaccination efficiency. Recent accumulating evidence indicates that immunosenescence underlies an increased proinflammatory trait with age, including various chronic inflammatory and metabolic disorders, such as atherosclerosis and diabetes mellitus, as well as an increased risk for autoimmunity. Cellular senescence is characterized by irreversible arrest of proliferation, grossly altered gene expression, and relative resistance to apoptosis. Notably, senescent cells are often metabolically active and may become foci of host reactions in tissues by secreting various inflammatory factors. The features and consequences of cellular senescence in T cells in the immune system, however, remain elusive.

One of the most prominent changes occurring in the immune organs with age is an early involution of the thymus. The thymus is a central immune organ to support T cell development and establish T cell self-tolerance. T cell generation in the thymus sharply declines after the juvenile stage, eventually replaced almost entirely by fat tissues at later stages of life. In concordance with the decrease of T cell genesis, the peripheral naïve T cells are gradually reduced with age. Although the peripheral T cell pool is well maintained in aged individuals, the population shows a steady increase in the proportions of memory phenotype (MP) T cells.

We reported that a unique PD-1+ MP CD4+ T cell population is increased with age, now termed senescence-associated (SA-) T cells. The SA-T cells show characteristic signs and features of cellular senescence and emerge as follicular T cells in spontaneous germinal centers (GCs) that occur in aged mice. Spontaneous development of GCs is a hallmark of systemic autoimmune diseases, and among a number of changes in immune function with age is an increasing risk for autoimmunity.

Progress Towards Ways to Make Old Stem Cells More Effective for Heart Repair

https://www.fightaging.org/archives/2018/05/progress-towards-ways-to-make-old-stem-cells-more-effective-for-heart-repair/

Stem cells in old tissues are less active than stem cells in young tissues, meaning a lesser supply of cells to maintain the tissue, and a consequent slow loss of function. The evidence to date suggest that a sizable part of this decline is a reaction to rising levels of tissue damage and the changing balance of cell signaling that results from that damage. There is certainly damage occurring to stem cells themselves, but that doesn’t appear to contribute to as great a degree until very late in life. This means that it is feasible to think about ways to force stem cells to get back to work, to rejuvenate their behavior if not their level of intrinsic damage, and assess the benefits against the potential risks, such as a higher rate of cancer. The stem cell therapies of the past few decades suggest that this cancer risk is lower than was expected, that evolution has left us more wiggle room for therapeutic enhancement of stem cell activity in the old than it might have done.

Ischemic heart disease affects a majority of people, especially elderly patients. Recent studies have utilized autologous adult stem cells and progenitor cells as a treatment option to heal cardiac tissue after myocardial infarction. However, donor cells from aging patients are more likely to be in a senescent stage. Rejuvenation is required to reverse the damage levied by aging and promote a youthful phenotype. This review aims to discuss current strategies that are effective in rejuvenating aging cardiac stem cells and represent novel therapeutic methods to treat the aging heart.

Recent literature mainly focuses on three approaches that aim to reverse cardiac aging: genetic modification, pharmaceutical administration, and optimization of extracellular factors. In vitro genetic modification can be used to overexpress or knock down certain genes and allow for reversal of the aging phenotype. Pharmaceutical administration is another approach that allows for manipulation of signaling pathways related to cell proliferation and cell senescence. Since the stem cell niche can contribute to the age-related decline in stem cell function, rejuvenation strategies also include optimization of extracellular factors.

Overall, improving the intrinsic properties of aging stem cells as well as the surrounding environment allows these cells to adopt a phenotype similar to their younger counterparts. Recent studies show promising results of the ability of these techniques to rejuvenate the aging heart. However, more understanding of the combinatorial effects of these interventions and fine-tuning of these techniques is required to evaluate the translational potential of these methods. Each strategy has its own advantages and disadvantages. The success of myocardial regenerative treatment will require teamwork across various disciplines to make stem cell therapy a reliable method for cardiac repair.

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Does Malformed Lamin A Produce Enough Cellular Senescence to Contribute Meaningfully to the Progression of Aging?

Progeria is one of the better known accelerated aging conditions. It isn’t actually accelerated aging, but rather one specific runaway form of cell damage that gives rise to general dysfunction in cells throughout the body. Since degenerative aging is also a matter of general dysfunction in cells throughout the body, there is some overlap in the observed results, even though the root causes are completely different. So progeria patients appear, superficially at least, to be prematurely aged, and die from heart disease early in life.

The cause of progeria was discovered to be a mutation in the Lamin A (LMNA) gene, resulting in a malformed protein now called progerin. This protein is an important structural component of the cell nucleus. If it doesn’t function correctly, the nucleus becomes misshapen, and near all processes involving nuclear DNA maintenance and gene expression – the production of needed proteins at the right time from their genetic blueprints – cease to work correctly. The cell becomes dysfunctional. When near all cells are in this state, the prognosis for the individual is dire. Interestingly, in the years since this discovery, it has become clear that progerin is also present in small amounts in genetically normal older individuals. There is some debate over whether or not this is important in the progression of aging. Does it cause enough damage, or is it insignificant in comparison to other harmful processes?

In this context, we can consider cellular senescence, a mechanism closely connected to DNA damage, by which a small number of problem cells can cause outsized amounts of harm. Another possibility is damage to stem cells, as they are also small in number but highly influential on tissue function. Cells become senescent in response to internal damage, including that produced by progerin, and then either self-destruct or linger to secrete a potent mix of inflammatory and other signals. It is these signals, the senescence-associated secretory phenotype, that allows a comparatively small number of cells to produce comparatively large problems. It is known that senescent cells are important in many age-related conditions, particular those with a strong inflammatory component. Is generation of progerin significant as a cause of cellular senescence in normal aging, however? In this open access paper, researchers consider some of the mechanisms involved.

GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A-mediated human mesenchymal stem cell aging

The LMNA gene encodes lamin and lamin C, which are major components of the nuclear lamina. Mutations in the LMNA gene have been implicated in premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). HGPS is caused by splicing defect and consequent generation of progerin, mutant-truncated lamin protein. Cells of HGPS patients exhibit an abnormal nuclear structure, increased DNA damage and premature senescence. In addition to the effects of progerin, accumulation of prelamin A, precursor of lamin A, induces defects in nuclear structures. ZMPSTE24 is an enzyme that produces mature lamin by cleavage of amino acids in prelamin A.

Zmpste24 knock-out mice have been widely used to study the mechanisms of aging and progeria. Depletion of Zmpste24 causes premature senescence in mice, including decreases in life span and bone density. Increased prelamin expression caused by ZMPSTE24 deficiency causes defective DNA repair. Zmpste24 knock-out mice have been extensively studied because of their impaired DNA damage response (DDR). Lamin also functions as a structural barrier to DDR. Altogether, these findings indicate that defects in the nuclear structure induced by progerin or prelamin lead to the accumulation of DNA damage, which results in accelerated aging.

It has been reported that exogenous expression of progerin in human mesenchymal stem cells (hMSCs) can impair their differentiation potential. Furthermore, production of induced pluripotent stem cells (iPSCs) from HGPS patients has revealed that the progerin expression levels are the highest in MSCs, vascular smooth muscle cells, and fibroblasts. These results indicate that MSCs are a specific target cell type of progerin-induced senescence. Like progerin, excessive accumulation of prelamin induces premature senescence in MSCs, including wrinkled nuclei. Downregulation of ZMPSTE24 in hMSCs also induces the senescence phenotype. These investigations imply that both progerin and prelamin can induce senescence in hMSCs with change in nuclear morphology.

Senescent cells secrete a group of factors that induce senescence in neighboring cells, a phenomenon termed senescence-associated secretory phenotype (SASP). The secreted inflammatory factors propagate senescence and recruit immune cells to senescent tissues by the generation of a pro-inflammatory environment. Among the factors reported to regulate the SASP, GATA4 has been recently identified as a regulator of senescence and inflammation. GATA4 is expressed during oncogene– and irradiation-induced senescence in fibroblasts in response to DNA damage. During the process of cellular senescence, GATA4 has a regulatory role in the SASP of fibroblasts. Because GATA4-dependent cellular senescence is closely associated with DDR, the role of GATA4 in other senescence models and other cell types may reveal a new mechanism.

Senescent hMSCs also induce senescence in neighboring cells. Monocyte chemoattractant protein-1 (MCP-1) secreted from senescent human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) induces premature senescence in neighboring cells. Insulin-like growth factor binding proteins are also produced by senescent hMSCs, and they trigger senescence in adjacent normal cells. These studies investigated the mechanisms of the SASP by inducing senescence in hMSCs through prolonged passaging. However, cellular senescence of MSCs can be regulated by various factors other than passaging. In our previous report, we have demonstrated that depletion of ZMPSTE24 and introduction of progerin induce premature senescence in hUCB-MSCs. It remains to be determined whether defective lamin triggers paracrine senescence via inflammatory factors in hMSCs.

In this study, we identified that paracrine senescence is triggered in senescent hMSCs with abnormal nuclear structures by increasing the expression of MCP-1 and that inhibition of MCP-1 decreases the SASP. Furthermore, we found that GATA4 mediates the senescence of hMSCs induced by defective lamin A. We assessed whether down-regulation of GATA4 disturbs the progerin- or prelamin A-dependent senescence phenotype. Elucidating how GATA4 regulates senescence in hMSCs with nuclear defects may aid in understanding the etiology of complex aging disorders. We show that inhibition of GATA4 expression protects hMSCs from cellular senescence, implying unique therapeutic opportunity against progeroid syndromes and physiological aging.

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Does Malformed Lamin A Produce Enough Cellular Senescence to Contribute Meaningfully to the Progression of Aging?

Progeria is one of the better known accelerated aging conditions. It isn’t actually accelerated aging, but rather one specific runaway form of cell damage that gives rise to general dysfunction in cells throughout the body. Since degenerative aging is also a matter of general dysfunction in cells throughout the body, there is some overlap in the observed results, even though the root causes are completely different. So progeria patients appear, superficially at least, to be prematurely aged, and die from heart disease early in life.

The cause of progeria was discovered to be a mutation in the Lamin A (LMNA) gene, resulting in a malformed protein now called progerin. This protein is an important structural component of the cell nucleus. If it doesn’t function correctly, the nucleus becomes misshapen, and near all processes involving nuclear DNA maintenance and gene expression – the production of needed proteins at the right time from their genetic blueprints – cease to work correctly. The cell becomes dysfunctional. When near all cells are in this state, the prognosis for the individual is dire. Interestingly, in the years since this discovery, it has become clear that progerin is also present in small amounts in genetically normal older individuals. There is some debate over whether or not this is important in the progression of aging. Does it cause enough damage, or is it insignificant in comparison to other harmful processes?

In this context, we can consider cellular senescence, a mechanism closely connected to DNA damage, by which a small number of problem cells can cause outsized amounts of harm. Another possibility is damage to stem cells, as they are also small in number but highly influential on tissue function. Cells become senescent in response to internal damage, including that produced by progerin, and then either self-destruct or linger to secrete a potent mix of inflammatory and other signals. It is these signals, the senescence-associated secretory phenotype, that allows a comparatively small number of cells to produce comparatively large problems. It is known that senescent cells are important in many age-related conditions, particular those with a strong inflammatory component. Is generation of progerin significant as a cause of cellular senescence in normal aging, however? In this open access paper, researchers consider some of the mechanisms involved.

GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A-mediated human mesenchymal stem cell aging

The LMNA gene encodes lamin and lamin C, which are major components of the nuclear lamina. Mutations in the LMNA gene have been implicated in premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). HGPS is caused by splicing defect and consequent generation of progerin, mutant-truncated lamin protein. Cells of HGPS patients exhibit an abnormal nuclear structure, increased DNA damage and premature senescence. In addition to the effects of progerin, accumulation of prelamin A, precursor of lamin A, induces defects in nuclear structures. ZMPSTE24 is an enzyme that produces mature lamin by cleavage of amino acids in prelamin A.

Zmpste24 knock-out mice have been widely used to study the mechanisms of aging and progeria. Depletion of Zmpste24 causes premature senescence in mice, including decreases in life span and bone density. Increased prelamin expression caused by ZMPSTE24 deficiency causes defective DNA repair. Zmpste24 knock-out mice have been extensively studied because of their impaired DNA damage response (DDR). Lamin also functions as a structural barrier to DDR. Altogether, these findings indicate that defects in the nuclear structure induced by progerin or prelamin lead to the accumulation of DNA damage, which results in accelerated aging.

It has been reported that exogenous expression of progerin in human mesenchymal stem cells (hMSCs) can impair their differentiation potential. Furthermore, production of induced pluripotent stem cells (iPSCs) from HGPS patients has revealed that the progerin expression levels are the highest in MSCs, vascular smooth muscle cells, and fibroblasts. These results indicate that MSCs are a specific target cell type of progerin-induced senescence. Like progerin, excessive accumulation of prelamin induces premature senescence in MSCs, including wrinkled nuclei. Downregulation of ZMPSTE24 in hMSCs also induces the senescence phenotype. These investigations imply that both progerin and prelamin can induce senescence in hMSCs with change in nuclear morphology.

Senescent cells secrete a group of factors that induce senescence in neighboring cells, a phenomenon termed senescence-associated secretory phenotype (SASP). The secreted inflammatory factors propagate senescence and recruit immune cells to senescent tissues by the generation of a pro-inflammatory environment. Among the factors reported to regulate the SASP, GATA4 has been recently identified as a regulator of senescence and inflammation. GATA4 is expressed during oncogene– and irradiation-induced senescence in fibroblasts in response to DNA damage. During the process of cellular senescence, GATA4 has a regulatory role in the SASP of fibroblasts. Because GATA4-dependent cellular senescence is closely associated with DDR, the role of GATA4 in other senescence models and other cell types may reveal a new mechanism.

Senescent hMSCs also induce senescence in neighboring cells. Monocyte chemoattractant protein-1 (MCP-1) secreted from senescent human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) induces premature senescence in neighboring cells. Insulin-like growth factor binding proteins are also produced by senescent hMSCs, and they trigger senescence in adjacent normal cells. These studies investigated the mechanisms of the SASP by inducing senescence in hMSCs through prolonged passaging. However, cellular senescence of MSCs can be regulated by various factors other than passaging. In our previous report, we have demonstrated that depletion of ZMPSTE24 and introduction of progerin induce premature senescence in hUCB-MSCs. It remains to be determined whether defective lamin triggers paracrine senescence via inflammatory factors in hMSCs.

In this study, we identified that paracrine senescence is triggered in senescent hMSCs with abnormal nuclear structures by increasing the expression of MCP-1 and that inhibition of MCP-1 decreases the SASP. Furthermore, we found that GATA4 mediates the senescence of hMSCs induced by defective lamin A. We assessed whether down-regulation of GATA4 disturbs the progerin- or prelamin A-dependent senescence phenotype. Elucidating how GATA4 regulates senescence in hMSCs with nuclear defects may aid in understanding the etiology of complex aging disorders. We show that inhibition of GATA4 expression protects hMSCs from cellular senescence, implying unique therapeutic opportunity against progeroid syndromes and physiological aging.

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Does Malformed Lamin A Produce Enough Cellular Senescence to Contribute Meaningfully to the Progression of Aging?

Progeria is one of the better known accelerated aging conditions. It isn’t actually accelerated aging, but rather one specific runaway form of cell damage that gives rise to general dysfunction in cells throughout the body. Since degenerative aging is also a matter of general dysfunction in cells throughout the body, there is some overlap in the observed results, even though the root causes are completely different. So progeria patients appear, superficially at least, to be prematurely aged, and die from heart disease early in life.

The cause of progeria was discovered to be a mutation in the Lamin A (LMNA) gene, resulting in a malformed protein now called progerin. This protein is an important structural component of the cell nucleus. If it doesn’t function correctly, the nucleus becomes misshapen, and near all processes involving nuclear DNA maintenance and gene expression – the production of needed proteins at the right time from their genetic blueprints – cease to work correctly. The cell becomes dysfunctional. When near all cells are in this state, the prognosis for the individual is dire. Interestingly, in the years since this discovery, it has become clear that progerin is also present in small amounts in genetically normal older individuals. There is some debate over whether or not this is important in the progression of aging. Does it cause enough damage, or is it insignificant in comparison to other harmful processes?

In this context, we can consider cellular senescence, a mechanism closely connected to DNA damage, by which a small number of problem cells can cause outsized amounts of harm. Another possibility is damage to stem cells, as they are also small in number but highly influential on tissue function. Cells become senescent in response to internal damage, including that produced by progerin, and then either self-destruct or linger to secrete a potent mix of inflammatory and other signals. It is these signals, the senescence-associated secretory phenotype, that allows a comparatively small number of cells to produce comparatively large problems. It is known that senescent cells are important in many age-related conditions, particular those with a strong inflammatory component. Is generation of progerin significant as a cause of cellular senescence in normal aging, however? In this open access paper, researchers consider some of the mechanisms involved.

GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A-mediated human mesenchymal stem cell aging

The LMNA gene encodes lamin and lamin C, which are major components of the nuclear lamina. Mutations in the LMNA gene have been implicated in premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). HGPS is caused by splicing defect and consequent generation of progerin, mutant-truncated lamin protein. Cells of HGPS patients exhibit an abnormal nuclear structure, increased DNA damage and premature senescence. In addition to the effects of progerin, accumulation of prelamin A, precursor of lamin A, induces defects in nuclear structures. ZMPSTE24 is an enzyme that produces mature lamin by cleavage of amino acids in prelamin A.

Zmpste24 knock-out mice have been widely used to study the mechanisms of aging and progeria. Depletion of Zmpste24 causes premature senescence in mice, including decreases in life span and bone density. Increased prelamin expression caused by ZMPSTE24 deficiency causes defective DNA repair. Zmpste24 knock-out mice have been extensively studied because of their impaired DNA damage response (DDR). Lamin also functions as a structural barrier to DDR. Altogether, these findings indicate that defects in the nuclear structure induced by progerin or prelamin lead to the accumulation of DNA damage, which results in accelerated aging.

It has been reported that exogenous expression of progerin in human mesenchymal stem cells (hMSCs) can impair their differentiation potential. Furthermore, production of induced pluripotent stem cells (iPSCs) from HGPS patients has revealed that the progerin expression levels are the highest in MSCs, vascular smooth muscle cells, and fibroblasts. These results indicate that MSCs are a specific target cell type of progerin-induced senescence. Like progerin, excessive accumulation of prelamin induces premature senescence in MSCs, including wrinkled nuclei. Downregulation of ZMPSTE24 in hMSCs also induces the senescence phenotype. These investigations imply that both progerin and prelamin can induce senescence in hMSCs with change in nuclear morphology.

Senescent cells secrete a group of factors that induce senescence in neighboring cells, a phenomenon termed senescence-associated secretory phenotype (SASP). The secreted inflammatory factors propagate senescence and recruit immune cells to senescent tissues by the generation of a pro-inflammatory environment. Among the factors reported to regulate the SASP, GATA4 has been recently identified as a regulator of senescence and inflammation. GATA4 is expressed during oncogene– and irradiation-induced senescence in fibroblasts in response to DNA damage. During the process of cellular senescence, GATA4 has a regulatory role in the SASP of fibroblasts. Because GATA4-dependent cellular senescence is closely associated with DDR, the role of GATA4 in other senescence models and other cell types may reveal a new mechanism.

Senescent hMSCs also induce senescence in neighboring cells. Monocyte chemoattractant protein-1 (MCP-1) secreted from senescent human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) induces premature senescence in neighboring cells. Insulin-like growth factor binding proteins are also produced by senescent hMSCs, and they trigger senescence in adjacent normal cells. These studies investigated the mechanisms of the SASP by inducing senescence in hMSCs through prolonged passaging. However, cellular senescence of MSCs can be regulated by various factors other than passaging. In our previous report, we have demonstrated that depletion of ZMPSTE24 and introduction of progerin induce premature senescence in hUCB-MSCs. It remains to be determined whether defective lamin triggers paracrine senescence via inflammatory factors in hMSCs.

In this study, we identified that paracrine senescence is triggered in senescent hMSCs with abnormal nuclear structures by increasing the expression of MCP-1 and that inhibition of MCP-1 decreases the SASP. Furthermore, we found that GATA4 mediates the senescence of hMSCs induced by defective lamin A. We assessed whether down-regulation of GATA4 disturbs the progerin- or prelamin A-dependent senescence phenotype. Elucidating how GATA4 regulates senescence in hMSCs with nuclear defects may aid in understanding the etiology of complex aging disorders. We show that inhibition of GATA4 expression protects hMSCs from cellular senescence, implying unique therapeutic opportunity against progeroid syndromes and physiological aging.

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