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  • There is No Such Thing as Aging
  • Targeting Senescent Cells to Reverse the Aging of the Heart
  • Delivery of T Cell Progenitor Cells as an Approach to Thymic Regeneration
  • Lamenting the Incomplete Understanding of Human Immunosenescence
  • Fecal Microbiota Transplantation from Old Mice to Young Mice Impairs Cognitive Function
  • Making the Leap from Mice to Humans in the Treatment of Aging
  • Senolytics as an Arm of Regenerative Medicine for the Elderly
  • The More Time Spent with High Blood Cholesterol, the Greater the Lifetime Risk of Heart Disease
  • Dopaminergenic Neurons Transplanted into Mouse Brains Integrate Into Neural Circuits and Improve Parkinson’s Symptoms
  • Lef1 Enables Skin Regeneration Without Scarring in Mice
  • Markers of Chronic Inflammation Correlate with Age-Related Loss of Muscle Mass and Strength
  • An Example of the Beneficial Role of Senescence in Injury
  • Klotho in Aging and the Failing Kidney
  • In Search of Common Transcriptional Regulators of Aging
  • Incorporating Microelectronics into Bioartificial Blood Vessels

There is No Such Thing as Aging

Today’s open access commentary is intended to provoke discussion on the topic of how aging is thought about and presented, particularly at the intersection between the scientific community and the rest of the world, or between scientific disciplines, or between scientists and funding institutions. It is an interesting read, as such commentaries often are.

Aging, of course, exists. It is a useful word that is applied as a bucket to hold a very complicated, ever-changing, and still comparatively poorly defined set of degenerative processes and the consequences of those processes. We age, we decline. That much is evident and right in front of our eyes. So a term will be invented and applied to it; we humans are nothing if not ruthless taxonomists.

In another sense, however, there is no such thing as aging. Aging is a fiction, like all abstractions, and it is frequently counterproductive to try to deal with the bucket rather than the inconveniently complex contents of the bucket. Focusing on an abstraction will lead one astray and distance one from the reality of the situation. That may well have been fine and possibly even helpful in the past, but it could be harmful at a time in which it is becoming possible to address the mechanisms that make up aging, to slow and reverse the consequences of those mechanisms.

What if there’s no such thing as “aging”?

Some years ago, it was argued that aging is not a biological phenomenon. The argument – that there are not necessarily common mechanisms underlying the major aging-related chronic diseases, such as cancer, but rather a suite of individual disease processes synchronized via natural selection – would surely find little favor today. Common mechanisms, including inflammaging, mitochondrial dysfunction, and cellular senescence, are now thought to be well established. In retrospect, the argument seems ignorant of aging mechanisms. Here, we argue that this apparently ignorant view is right, but for the wrong reasons: that our more detailed knowledge of aging mechanisms is increasingly showing that there is no unitary phenomenon usefully summarized with the word aging.

What is aging? This question, at the heart of our field, has received a great deal of attention, and many definitions, implicit or explicit, have been proposed. (Here, we use the term “aging,” though all our arguments equally apply to the term “senescence,” which is favored by some). A coherent definition is even essential for the field: there are intensive efforts to measure aging, to slow aging, and to treat aging, and it will be impossible to know if they are succeeding without a clear definition of the subject of our research. Is it accumulation of molecular damage? Is it loss of function with increasing age? Is it increases in mortality (or decreases in reproductive rate) with age? Underlying the discussion to date is an assumption so basic it goes unnoticed: that there is an underlying biological phenomenon of aging.

We have a word for aging, and therefore we assume that science will accommodate us, providing a phenomenon to match our word. And in a colloquial sense this is certainly the case: no one can doubt that we see ourselves, our relatives, and our friends age. But is this colloquial usage scientifically justified? Is there really a “thing” or a phenomenon we can call aging? We argue here that our understanding of the biology is now sufficient to say definitively that this is not the case, that from a scientific perspective there is no such thing as aging, but rather a collection of disparate phenomena and mechanisms – sometimes interacting with each other – that relate in one way or another to our colloquial sense of the word. Accordingly, our desire to find a single reality of aging has created a great deal of confusion in the field.

We are well aware that not all researchers in our field will like our thesis here: our identity as “aging researchers” is tightly wrapped around the notion that there is a phenomenon of aging. However, we do not believe there is a need to feel any existential threat from this idea, which is in some sense a natural extension of the multi-factorial hallmarks of aging or pillars of aging framework. Rather, we think that being more careful about our underlying assumptions, and how they do or do not conform to biological reality, can only make us better researchers. The field of aging research can still exist, but with a more nuanced understanding that we are not studying a single biological phenomenon, but an assortment of loosely related processes that we find convenient to lump together.

Targeting Senescent Cells to Reverse the Aging of the Heart

Almost a decade has passed since the first compelling demonstration that clearance of senescent cells in mice could produce rejuvenation. This validated decades of prior evidence, largely ignored in the research community, indicating that accumulation of senescent cells is a significant cause of degenerative aging. It was a wake-up call. Since then, numerous research groups have shown that targeted clearance of senescent cells reverses many age-related conditions and extends healthy life span in mice. It is easy to accomplish in the lab. Near any approach works, to the degree that it can destroy senescent cells without harming normal cells. As a consequence, a new biotech industry has come into being, a range of startups and programs working on clinical development of the first generation of senolytic drugs capable of safely removing senescent cells from aged tissues.

As a result of this field of research, it has been shown that accumulation of senescent cells is an important part of the development of cardiovascular disease. Senescent foam cells accelerate the progression of atherosclerosis, driving the growth of fatty lesions that narrow and weaken blood vessels, leading to stroke and heart attack. Senescent cells drive the calcification of blood vessels, and degrade the function of smooth muscle tissue in blood vessel walls. Senescent cells are a part of the dysfunction that leads to cardiac hypertrophy, the enlargement and weakening of heart muscle that causes heart failure, as well as fibrosis, a disruption of tissue structure by inappropriate collagen deposits. We now know all of this because it is possible to run animal studies in which senolytic treatments remove senescent cells, and then observe the result – a reversal of age-related cardiovascular disease.

Therapeutic Potential of Senolytics in Cardiovascular Disease

The most significant determining factor of cardiovascular health is a person’s age, with cardiovascular disease (CVD) being the leading cause of death in 40% of individuals over 65 years. The ageing heart undergoes a process of myocardial remodelling, which is characterised by physiological and molecular alterations that result in endothelial stenosis, vasomotor dysfunction and stiffening, cardiomyocyte hypertrophy, myocardial fibrosis, and inflammation which result in increased ventricular stiffness, impaired cardiac function and can ultimately lead to HF. In particular, HF with preserved ejection fraction (HFpEF), characterised by diastolic ventricular dysfunction with maintained systolic function, is clinically associated with ageing.

The association between senescence and myocardial ageing in humans has been reported for nearly 20 years. More recently it has been demonstrated that senescence contributes directly to age-related myocardial remodelling in mice, as pharmacogenetic elimination of senescent cells, using the p16-INKATTAC model, reduced myocardial fibrosis, and attenuated cardiomyocyte hypertrophy. Elimination of senescent cells from aged p16-INKATTAC mice also increased their survival and reduced the development of cardiac dysfunction following isoproterenol-induced myocardial stress. Following on from this data, we and others have hypothesised that an accumulation of senescence and the expression of a senescence-associated secretory phenotype (SASP) drive age-related myocardial remodelling and have begun to independently investigate if senolytics can eliminate senescent cell populations resident in the aged heart in order to improve myocardial function.

Pharmacological elimination of senescent cells from aged mice could improve myocardial function. Treatment of 24-month-old mice with a single dose of dasatinib and quercetin significantly improved left ventricular (LV) ejection fraction and fractional shortening. This observed change in function was suggested to be a result of a restoration in vascular endothelial function. We have shown in aged mice that senescence occurred primarily within the cardiomyocyte population and led to the expression of a cardiomyocyte-specific SASP with the potential to promote myofibroblast differentiation of fibroblasts and induce cardiomyocytes to hypertrophy in vitro. In vivo, cyclical oral administration of navitoclax reduced the number of senescent cardiomyocytes, attenuated components of the cardiomyocyte SASP and reduced myocardial remodelling as indicated by a reduction in both cardiomyocyte hypertrophy and interstitial fibrosis.

Given the limited regenerative capacity of the heart, there is considerable interest in the potential of regenerative cellular therapies for the treatment of CVD such as myocardial infarction (MI) and age-related HF. For cellular therapies to be effective, the grafted cells must survive, integrate, and function within the surviving myocardium. The data discussed above suggest that older age not only increases the potential for dysfunction in the very populations that are being used for cellular therapies but also increases the hostility of the recipient myocardial environment as a result of SASP mediated inflammation and the bystander effect. This may in part explain the failure of pre-clinical trials to translate clinically into regenerative therapies. Preclinical studies showing successful cell regenerative therapies use young healthy animals, whereas the prevalence of CVD increases linearly with age, and therefore, most patients undergoing cellular therapy are likely to display high levels of myocardial senescence which could create an unfavourable environment impeding incorporation and differentiation of the transplanted cell populations. Senolytic-mediated elimination of senescent cells from aged patients may, therefore, have the potential to improve the outcomes of such regenerative cellular therapies.

Delivery of T Cell Progenitor Cells as an Approach to Thymic Regeneration

The thymus is a small organ in which thymocytes generated in the bone marrow mature to become T cells of the adaptive immune system. Unfortunately, the thymus atrophies with age, its active tissue largely replaced by fat in most people by age 50 or so. Thereafter the adaptive immune system declines into immunosenescence and inflammaging, deprived of a sufficiently large supply of reinforcement cells. Given the importance of the immune system to health, in matters including tissue maintenance, resistance to infection, suppression of cancer, and more, regeneration of the thymus must be an important component of any serious effort to rejuvenate the elderly. Numerous approaches have been proposed, shown to work in mice, and some even attempted or demonstrated in humans, but this isn’t yet a solved problem.

One important class of approach to thymic regeneration is the delivery of cells that will home to the thymus. These cells can in principle be delivered via simple intravenous injection, rather than requiring a much more invasive introduction into the thymus directly. Once in the thymus they either directly assist in building new tissue, or deliver signals that encourage native stem cells to stop slacking and regenerate the thymus. An example of the type is the delivery of epithelial progenitor cells, demonstrated to produce thymic growth in mice a few years ago. Another example, as outlined in today’s open access paper, is to deliver cells that are somewhere in the lineage that starts with thymocytes and ends at T cells, as these will also home to the thymus, and their signaling encourages greater thymic activity. The cross-talk between hematopoietic cells in the bone marrow and the thymus is likely mediated by these cells and their signals.

Thymic Engraftment by in vitro-Derived Progenitor T Cells in Young and Aged Mice

T cells play a critical role in mediating antigen-specific and long-term immunity against viral and bacterial pathogens, and their development relies on the highly specialized thymic microenvironment. T cell immunodeficiency can be acquired in the form of inborn errors, or can result from perturbations to the thymus due to aging or irradiation/chemotherapy required for cancer treatment. Hematopoietic stem cell (HSC) transplant (HSCT) from compatible donors is a cornerstone for the treatment of hematological malignancies and immunodeficiency. Although it can restore a functional immune system, profound impairments exist in recovery of the T cell compartment. T cells remain absent or low in number for many months after HSCT, depending on a variety of factors including the age of the recipient.

While younger patients have a shorter refractory period, the prolonged T cell recovery observed in older patients can lead to a higher risk of opportunistic infections and increased predisposition to relapse. Thus, strategies for enhancing T cell recovery in aged individuals are needed to counter thymic damage induced by radiation and chemotherapy toxicities, in addition to naturally occurring age-related thymic involution.

Preclinical results have shown that robust and rapid long-term thymic reconstitution can be achieved when progenitor T cells, generated in vitro from HSCs, are co-administered during HSCT. Progenitor T cells appear to rely on lymphostromal crosstalk via receptor activator of NF-κB (RANK) and RANK-ligand (RANKL) interactions, creating chemokine-rich niches within the cortex and medulla that likely favor the recruitment of bone marrow-derived thymus seeding progenitors. Here, we employed preclinical mouse models to demonstrate that in vitro-generated progenitor T cells can effectively engraft involuted aged thymuses, which could potentially improve T cell recovery. The utility of progenitor T cells for aged recipients positions them as a promising cellular therapy for immune recovery and intrathymic repair following irradiation and chemotherapy, even in a post-involution thymus.

Lamenting the Incomplete Understanding of Human Immunosenescence

The immune system is inconveniently complicated. Aging is also inconveniently complicated. The overlap between the two is a particularly dark forest for the research community, with few well-tracked paths. The fine details of how exactly the immune system becomes dysfunctional with age, and the sizable variation in those details between individuals, will keep research teams occupied for decades to come. It seems very plausible that here, as elsewhere in the study of aging, effective rejuvenation therapies that turn back immune aging will precede a strong understanding of how they produce benefits.

For example, it is fairly clear that here are harmful populations of immune cells, and that selectively destroying them produces benefits in old individuals. Age-associated B cells accumulate over time to cause numerous issues. When the B cell population is entirely destroyed it is rapidly replaced, even in late life, with new cells that lack the harmful behaviors of their predecessors. Similarly, it is fairly clear that having too few naive T cells capable of tackling new threats is damaging to health. The supply and reserve of such cells diminish with age due to atrophy of the thymus and incapacity of hematopoietic stem cell populations. Restoring the thymus or hematopoietic activity has been shown to improve immune function.

In both of those cases, there is a surrounding halo of unknowns regarding how and why problem cells arise, or the thymus atrophies, or hematopoietic stem cells become damaged and quiescent. The types of treatment proposed are very much engineering solutions: cut the Gordian knot of a lack of knowledge by enacting what appears to be the best solution and examining the consequences. When it works well in animal models, trial it in humans, is the philosophy. The scientific community is made somewhat uncomfortable by this sort of approach, however. The scientific impulse is, correctly, always in the direction of greater knowledge and greater understanding of exactly how a system works, fails, or is repaired. But we cannot let that impulse rule to the exclusion of building rejuvenation therapies that can work now, to the extent that we can do so, in advance of a full and complete understanding of immune aging.

The conundrum of human immune system “senescence”

Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as “immunosenescence”. But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity.

Demonstrating which changes of immune ageing are in fact associated with detrimental health outcomes and only then trying to restore them to an appropriate level may indeed be theoretically desirable. However, prior to establishing which are truly detrimental, rather than merely different in aged individuals, such intervention would be premature, and in some cases might be dangerous. One has to say that with this in mind most such efforts are indeed premature because we do not know which parameters to take as biomarkers reflecting these changes, and mistakenly attempting to “correct” adaptive changes would be undesirable. Hence, there is an argument in favour of attempts to classify such biomarkers of senescence in ageing in general, and even more challengingly in immunosenescence in particular, in order to generate actionable entities for treatment.

A consensus from published studies delineates one immune parameter consistently reported to be different between younger and older adults, namely the very low absolute and relative counts of naïve CD8+ T cells in the peripheral blood of older adults. This is not to say the older adults actually do possess fewer naïve T cells because data on the presence of immune cells in other organs are mostly lacking and most data pertain only to circulating cells. However, the expectation is that the whole-body number of CD8+ naïve T cells is indeed low, due to markedly reduced thymic output and cell mortality owing to a lifetime´s exposure to pathogens, agreeing with data from animal models. Reciprocally, it would be expected that because antigen-stimulated naïve cells differentiate into effector and memory cells, the latter would be increased in older adults, as also often reported. It is thus somewhat surprising that CD8+ memory cell accumulation in the blood of older adults is not universally reported. It has become apparent in the meantime that the accumulations of late-stage memory cells that are seen in older people are driven by persistent infection with cytomegalovirus (CMV), but apparently not by other herpesviruses or other pathogens. These sometimes disputed findings have been confirmed in systematic reviews.

Despite differences in many immune parameters between men and women, in the few studies examining this issue, the markedly lower levels of circulating CD8+ naïve T cells have been found in both sexes, further emphasising the universality of these findings. Intriguingly, although present, age-associated differences for CD4+ naïve T cells, B cells, and many aspects of innate immunity, especially dendritic cells (DCs) and neutrophils, are much less marked than for CD8+ T cells, one of the enduring mysteries in immunosenescence research. Again, it should be emphasized that the majority of immune cells resides in tissues and not in blood, and that the latter most likely does not reflect patterns of cell subset distribution elsewhere

Immune parameters assessed in cross-sectional studies clearly document multiple differences between younger and older populations. Animal studies as well as some more limited longitudinal studies in humans indicate that many of these differences are indeed likely to be intra-individual age- and environment-associated changes. Some immune signatures established as subject to distinct changes with age can be associated with important health outcomes such as frailty and responses to vaccination, and finally, with mortality. Many others are clearly hallmarks of the adaptation to exposures over the lifespan and continue to play a positive role in maintaining organismal integrity. Many may be informative only in the population in which they were assessed, and the search for truly universal age-associated changes in immune markers is ongoing. Whether these exist as reflections of ageing processes per se is open to question. Thus far, they mostly seem limited to reductions in numbers, proportions and the antigen receptor repertoire of peripheral blood naïve T cells and other immune cells. In turn, this reflects thymic involution at puberty and the degree of residual thymic function in later life, as well as possibly dysfunctional haematopoiesis and the poorly defined detrimental systemic milieu in older individuals which remains mysterious.

Fecal Microbiota Transplantation from Old Mice to Young Mice Impairs Cognitive Function

The microbiome of the gut changes with age, and this is presently thought to have a meaningful influence over the course of aging. It is perhaps in the same ballpark as the effects of exercise on the pace of aging and risk of age-related disease, and certainly overlaps with the effects of diet, particularly that of calorie restriction. In general, aging is accompanied by a reduction in beneficial microbial species that produce metabolites known to improve cell and tissue function, such as butyrate, propionate, and indoles. Equally, harmful inflammatory microbial species grow in numbers, and contribute to the chronic inflammation that characterizes aging, disrupting tissue maintenance and accelerating the progression towards age-related disease.

Today’s open access paper is a representative example of a broad range of present work that attempts to quantify the degree to which age-related changes in the gut microbiome are harmful. There are two ways to go about this, involving fecal microbiota transplantation from either (a) old to young animals and looking for harms, or (b) from young to old animals and looking for benefits. The former is the case here, and researchers quite credibly show that an old microbiome impairs cognitive function in young mice.

What is to be done about the aging of the gut microbiome? The most plausible path forward is to adapt the existing use of fecal microbiota transplantation in human medicine in order to transplant material from young donors into older individuals. In medical conditions in which the intestine is overtaken by harmful pathogens, this treatment can be a lasting cure: the balance of species in the gut is permanently changed in these cases. Lasting reversal of the impaired state of an old microbiome also appears possible via transplantation from a young individual, based on work conducted in short-lived species such as killifish. It is a promising approach, but is not at present receiving the level of interest required for clinical development to move ahead.

Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients

The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions.

Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour, and locomotor activity remained unaffected.

This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected.

These results demonstrate that age-associated shifts of the microbiota have an impact on protein expression and key functions of the CNS. Furthermore, these results highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions and the declining quality of life in the elderly.

Making the Leap from Mice to Humans in the Treatment of Aging

This commentary makes the point that the development of interventions to slow and reverse aging is moving along at some pace in mice, the field expanding year after year, but the translation of this work into human medicine is very definitely lagging behind, yet to come up to speed. This is largely true for any comparatively new and growing field of medicine, given the enormous and excessive cost and delay imposed by regulators, but the study of aging has its own peculiarities in addition to that issue. For example, the lack of a good way to measure the outcome of a treatment on the mechanisms and progression of aging. Or the strong focus on approaches such as upregulation of the stress response mechanisms of autophagy, wherein the effects on aging and life span are much more pronounced in short-lived species, leading to comparatively poor results in humans. There will be a point at which the medical side of the field of aging research catches up, certainly, but exactly when that will start to happen is an open question.

Almost a century has passed since Clive McCay discovered that reducing the food intake of his rats increased their lifespan by up to 40%. Now we know that dozens of interventions extend the lifespan of organisms such as rodents, nematodes, yeast, and fruit flies. Aging is not as static as it once seemed. Clearly, we now know that several conserved molecular changes occur in organisms with age and we have developed interventions in animal models to impact almost all of them. Nevertheless, despite our great push for testing lifespan and healthspan altering molecules and growing knowledge of the underlying causes of aging, we still do not know if most of our interventions will work in humans. Why is that?

A major problem facing the field of aging is measuring the effect of an intervention. In short lived organisms such as fruit flies, nematodes, and yeast, effects are easy to measure simply by investigating how an intervention impacts the lifespan. However, with longer lived organisms this becomes challenging and surrogate markers are therefore needed that reflect biological aging. Ten years ago, the identification of single biomarkers of aging was a grand challenge when considering trials for aging in humans, however, landmark papers have since shown that we can quite accurately measure age by looking at the combined alterations in the epigenetic landscape. We can then use these biomarkers to test if we can reduce or reverse the biological age of an individual. With these tools at our disposal, we have truly moved into an era where biomarkers are no longer an issue.

Concurrent with the recent development in biomarkers the first trials targeting aging in humans are now being started. The need for testing a significant number of individuals have been a limiting factor for trial designs. This has been the case because trials are often designed for mortality endpoints or other relatively rare events for otherwise healthy elderly individuals which necessitates large cohorts. Based on recent trials, it appears that even relatively short treatments may be enough to see signs of epigenetic age-reduction in humans, however. In summary, we have all the tools available to begin transitioning to testing in humans.

Twenty years ago, the NIA funded Interventions Testing Program (ITP) was conceived to test interventions in mice with the specific goal of translating the findings to clinical trials in human. The program, which investigates the lifespan effect of proposed interventions in genetically diverse mice across multiple centers, has been a massive success with numerous groundbreaking findings, perhaps most notoriously the discovery that rapamycin extends the lifespan of mice. Nevertheless, the hope of real translation was never completely carried forward to humans even though some trials have been examining the effect of compounds such as rapamycin on age-associated diseases, but not aging itself. To tackle our grand challenge, I propose that the field funds a human interventions testing program that will investigate promising compounds in humans.

Senolytics as an Arm of Regenerative Medicine for the Elderly

Senolytic therapies are those that selectively destroy the senescent cells that accumulate in tissues with age. These cells secrete a potent mix of signals that produce chronic inflammation and degrade tissue function, particularly the ability of tissues to maintain and repair themselves. While many well known interventions that improve long-term health – exercise, calorie restriction, and so forth – are likely to modestly lower the burden of senescent cells over time, by increasing the pace of destruction or lowering the pace of creation, the senolytic label is reserved for therapies that can be applied to very quickly destroy a significant number of such cells. Animal studies suggest that removing as little as a third of the senescent cells in an old individual, via treatments such as the dasatinib and quercetin combination, is enough to produce quite profound reversal of pathology in numerous age-related diseases. A higher degree of clearance should be better.

Researchers are probing ways to activate the body’s regenerative potential to slow the clock on chronic conditions that set in as we age. “We’re quite interested in what it is it about aging that compromises the ability of our bodies to rejuvenate. We want to know what it is about the process of aging that leads to the molecular and cellular damage associated with different diseases and geriatric syndromes.”

Cell senescence, a state of growth arrest, plays a key role in aging. Damage to cells, and particularly their DNA, due to natural aging processes or environmental factors such as cigarette smoke, causes cells to become senescent. Senescent cells no longer divide and differentiate. They then lose their ability to repair tissue. Senescent cells secrete harmful proteins and chemicals, creating sort of a “toxic soil” locally, if not globally, that disrupts the function of stem cells. That can sap the body’s ability to heal from injury. Though senescent cells are relatively few, they accumulate with advancing age. Ultimately, they contribute to disease and failing health.

“What’s interesting about a senescent cell, is it is a robust secretory factory, if you will, pumping out cytokines, chemokines, and other factors into the local environment that creates all kinds of havoc. It compromises the health and function of neighboring cells and the surrounding tissue. In the field of aging, we often talk about inflammation as a primary cause of disease. Factors secreted by senescent cells clearly contribute to a state of chronic sterile inflammation, or a smoldering fire, which can burst into a conflagration and drive disease.”

“We’ve published one study that in at least the context of obesity, finds exercise can prevent senescent cell accumulation and, to some extent, clear senescent cells from the body. Exercise has profound effects on our cells and their capacity to repair different aspects of cell damage that are linked to aging and age-related diseases. For example, exercise improves the cells’ ability to repair DNA, manage oxidative stress, and turn on the garbage disposal and get rid of old damaged proteins.”

The More Time Spent with High Blood Cholesterol, the Greater the Lifetime Risk of Heart Disease

Researchers here suggest that the processes of atherosclerosis, leading to the buildup of fatty deposits that narrow and weaken blood vessels, are cumulative over time. One of the risk factors is high blood cholesterol, and high cholesterol in youth is found to correlate with increased risk in later life, even if blood cholesterol has been restored to normal levels at that time. This is interesting, as the cause of atherosclerosis is less blood cholesterol per se and more the oxidized cholesterol that disrupts the function of macrophage cells responsible for cleaning up cholesterol in blood vessel walls. Those macrophages should be working just fine in genetically normal young people with high cholesterol, as oxidized cholesterol is a feature of aging, and should be only minimally present in the young. This suggests that perhaps the researchers are seeing the ongoing, lifetime effects of the sort of neglect of health that is required to obtain high blood cholesterol when young, rather than a specific disease process.

An ongoing study, funded by the National Heart, Lung, and Blood Institute, began 35 years ago, recruiting 5,000 young adults aged 18 to 30. Researchers have tracked this cohort ever since to understand how individual characteristics, lifestyle, and environmental factors contribute to the development of cardiovascular disease later in life. “We found having an elevated LDL cholesterol level at a young age raises the risk of developing heart disease, and the elevated risk persists even in those who were able to later lower their LDL cholesterol levels. Damage to the arteries done early in life may be irreversible and appears to be cumulative. For this reason, doctors may want to consider prescribing lifestyle changes and also medications to lower high LDL cholesterol levels in young adults in order to prevent problems further down the road.”

To conduct the study, the researchers used complex mathematical modeling to understand how cardiovascular risk (heart attack, stroke, blood vessel blockages, and death from cardiovascular disease) rises with increasing cumulative “exposure” to LDL cholesterol over an average of 22 years. They found that the greater the area under the “LDL curve” – which measured time of exposure and level of LDL cholesterol over time – the more likely participants were to experience a major cardiovascular event. While the medical establishment understands the importance of managing high LDL cholesterol levels to lower heart risks, there is little consensus on how aggressively to intervene in young adults who may not experience a heart attack or stroke for decades.

Dopaminergenic Neurons Transplanted into Mouse Brains Integrate Into Neural Circuits and Improve Parkinson’s Symptoms

Researchers here demonstrate that human dopaminergenic neurons, the class of cell lost in Parkinson’s disease, can integrate into neural circuits and improve motor function when transplanted into mice. The challenge with all such cell therapies, in which cell replacement and consequent functional improvement is the goal, is that it is very hard to achieve any significant survival of cells following transplantation. Finding the right methodology has been a challenge, so proof of concept work like this is more important for the precise details of the methodology used – not discussed here – than for the outcome.

Researchers demonstrated a proof-of-concept stem cell treatment in a mouse model of Parkinson’s disease. They found that neurons derived from stem cells can integrate well into the correct regions of the brain, connect with native neurons and restore motor functions. The key is identity. By carefully tracking the fate of transplanted stem cells, the scientists found that the cells’ identity – dopamine-producing cells in the case of Parkinson’s – defined the connections they made and how they functioned. Coupled with an increasing array of methods to produce dozens of unique neurons from stem cells, the scientists say this work suggests neural stem cell therapy is a realistic goal.

To repair damaged neural circuits in the Parkinson’s disease mouse model, the researchers began by coaxing human embryonic stem cells to differentiate into dopamine-producing neurons, the kind of cells that die in Parkinson’s. They transplanted these new neurons into the midbrains of mice, the brain region most affected by Parkinson’s degeneration. Several months later, after the new neurons had time to integrate into the brain, the mice showed improved motor skills. Looking closely, researchers were able to see that the transplanted neurons grew long distances to connect to motor-control regions of the brain. The nerve cells also established connections with regulatory regions of the brain that fed into the new neurons and prevented them from being overstimulated.

Both sets of connections – feeding in and out of the transplanted neurons – resembled the circuitry established by native neurons. To confirm that the transplanted neurons had repaired the Parkinson’s-damaged circuits, the researchers inserted genetic on-and-off switches into the stem cells. These switches turn the cells’ activity up or down when they are exposed to specialized designer drugs in the diet or through an injection. When the stem cells were shut down, the mice’s motor improvements vanished.

Lef1 Enables Skin Regeneration Without Scarring in Mice

To achieve regeneration without scarring is an important goal in the medical research community. Some species are capable of proficient regeneration of even whole limbs or internal organs, but mammalian regeneration is stunted by comparison, sidetracked into the process of scar formation. This is likely a side-effect of processes that act to reduce cancer incidence, but researchers have not yet achieved a sufficiently comprehensive understanding of regeneration in species with different capabilities to be certain. Here, researchers note a demonstration of skin regeneration without scarring, produced by upregulation of the lef1 transcription factor. Studies of this nature can help to focus scientific investigations into more productive directions, narrowing down areas of interest in the cellular biochemistry of regeneration.

Researchers have identified a factor that acts like a molecular switch in the skin of baby mice that controls the formation of hair follicles as they develop during the first week of life. The switch is mostly turned off after skin forms and remains off in adult tissue. When it was activated in specialized cells in adult mice, their skin was able to heal wounds without scarring. The reformed skin even included fur and could make goose bumps, an ability that is lost in adult human scars.

Researchers used a new technique called single cell RNA sequencing to compare genes and cells in developing skin and adult skin. In developing skin, they found a transcription factor – proteins that bind to DNA and can influence whether genes are turned on or off. The factor the researchers identified, called Lef1, was associated with papillary fibroblasts which are developing cells in the papillary dermis, a layer of skin just below the surface that gives skin its tension and youthful appearance.

When the researchers activated the Lef1 factor in specialized compartments of adult mouse skin, it enhanced the skins’ ability to regenerate wounds with reduced scarring, even growing new hair follicles that could make goose bumps. Researchers first got the idea to look at early stages of mammalian life for the capacity to repair skin because after emergency life-saving surgery in utero, it was observed that when the babies were born they did not have any scars from the surgery. A lot of work still needs to be done before this latest discovery in mice can be applied to human skin, but it is an important advance.

Markers of Chronic Inflammation Correlate with Age-Related Loss of Muscle Mass and Strength

Chronic inflammation is a sizable component of aging. The immune system becomes inappropriately overactive, disrupting its normal participation in tissue maintenance, and producing alterations in the signaling environment that change the behavior of other cells for the worse. Inflammation appears to be important in the age-related decline of stem cell activity, for example. It is certainly important in the maintenance of muscle tissue. The study here is far from the only one to show a link between chronic inflammation and the age-related loss of muscle mass and strength, a condition known as sarcopenia.

Skeletal muscle plays an integral role in maintaining homeostasis across organ systems. Skeletal muscle is plastic, changing dynamically in response to physical activity, load, injury, illness, and ageing. The age-related loss of skeletal muscle strength, muscle mass, and physical performance (sarcopenia), has been associated with falls and fractures in older populations, and remains a largely undiagnosed condition. Beyond ageing, sarcopenia is associated with age-related diseases such as dementia, chronic obstructive pulmonary disease, and cardiovascular disease. In older adults, several of these diseases coincide with decline in muscle mass and whether this is caused by ageing or disease is largely unknown. However, a common feature underlying both conditions is inflammation.

Chronic inflammation, characterised by higher systemic cytokine and acute phase protein circulation, is not only linked to ageing ‘inflammaging’ but also muscle mass loss. Tumor necrosis factor α (TNFα) released from diseased tissues has been shown to exert endocrine effects on skeletal muscle. In vitro studies have shown that TNFα is a key endocrine stimulus for contractile dysfunction in chronic inflammation and that the muscle derived reactive oxygen species (ROS) and nitric oxide (NO) participate in depressing specific force of muscle fibre, which can lead to muscle atrophy. Furthermore Interleukin (IL)-6, a key cytokine involved in low-grade chronic inflammation, has been shown to facilitate muscle atrophy via blunting muscle anabolism and energy homeostasis.

The aim of this systematic review and meta-analysis was to determine the relationship between systemic inflammation, muscle strength, and/or muscle mass in adults. Overall, 168 articles; 149 cross-sectional articles (n = 76,899 participants, 47.0% male) and 19 longitudinal articles (n = 12,295 participants, 31.9% male) met inclusion criteria. Independent of disease state, higher levels of C reactive protein (CRP), Interleukin (IL)-6, and Tumor necrosis factor (TNF)α were associated with lower handgrip and knee extension strength and muscle mass. Furthermore, higher levels of systemic inflammatory markers appeared to be associated with lower muscle strength and muscle mass over time.

An Example of the Beneficial Role of Senescence in Injury

Researchers here provide an interesting demonstration of the beneficial role of transient cellular senescence in injury. Applying senolytics to selectively destroy senescent cells after traumatic injury is shown to greatly worsen the consequences. Senescent cells are harmful when they build up and linger in tissues over the course of later life. The signaling they generate is useful in the short-term, such as by mobilizing the response to injury in numerous cell populations, but very damaging when sustained for the long term. This dynamic is one of the reasons why we should favor infrequent senolytic therapies that destroy only the harmful, lingering senescent cells, rather than continuing treatments that would negatively impact regeneration and other functions by also destroying transient senescent cells.

It’s called senescence, when stressed cells can no longer divide to make new cells, and it’s considered a factor in aging and in some diseases. Now scientists have some of the first evidence that at a younger age at least, senescent cells show up quickly after a major injury and are protective. Their model is hemorrhagic shock, a significant loss of blood and the essential oxygen and nutrients it delivers that accounts for about 30-40% of trauma-related deaths from things like car accidents and shootings; and their focus the liver, one of the many major organs that can fail in response.

Shortly after hemorrhagic shock occurs, a population of liver cells quickly become senescent. To find out if the rapid movement to senescence they saw for some liver cells was good or bad, researchers gave some of the rats in their studies senolytics, a relatively new class of drugs that target senescent cells for elimination. Laboratory studies of these drugs have shown they can prevent or improve age-related problems like frailty, cataracts, and vascular and heart dysfunction. Early trials in humans have also reported success in reducing the progression of problems like diabetes and kidney related damage.

But when younger rats in hemorrhagic shock were given the drugs as part of the fluids used for resuscitation shortly after blood loss, they all quickly died. When the researchers gave the same senolytics to healthy rats, they were fine. Death of the senescent cells appears to exacerbate the tissue injury resulting from blood loss. Researchers suspect the rapid transition to senescence that occurred in a population of liver cells was an attempt to stabilize after the trauma, and likely transient. While he says you can’t generalize that what happens in one tissue, like the liver, will happen in another organ, the researchers expect something similar happens in other organs in the face of serious injury.

Klotho in Aging and the Failing Kidney

Klotho is one of the few longevity-associated genes with robustly demonstrated effects in both directions: reduce its expression and life span is reduced, increase its expression and life span is increased. Klotho levels decline with age, and this decline is strongly associated with loss of cognitive function, but, interestingly, this may be a very indirect effect that exists due to klotho’s influence over kidney function in aging. More klotho implies a slower decline in kidney function, and loss of kidney function is also shown to be a contributing factor in cognitive decline. Thus there is some interest in the research community in developing therapies based on delivery of klotho to patients; Unity Biotechnology added klotho to its otherwise senolytics-focused pipeline last year, for example.

Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology.

Klotho expression levels and its circulating level decline during aging. In humans, Klotho deficiency features medial calcification, intima hyperplasia, endothelial dysfunction, arterial stiffening, hypertension, impaired angiogenesis, and vasculogenesis (i.e., characteristics of early vascular aging). As Klotho-deficient phenotypes have been attenuated and rescued by Klotho gene expression, or supplementation, it is suggestive that Klotho has a protective effect with regard to the vasculature.

A range of strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists, and indirect approaches, via modulation of diet and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes of aging.

In Search of Common Transcriptional Regulators of Aging

Are there common regulators of aging to be found among transcription factors? Sweeping, complex, tissue-specific and species-specific changes in gene expression take place over the course of aging. If these are reactions to comparatively straightforward processes of molecular damage at the root of aging, processes that are similar between species, then it is possible that there also exist at least a few regulators that are also comparatively straightforward and similar between species. Where is the leap from simplicity to complexity? Is it that the immediate reaction to damage is complicated, with a hundred different sensors and systems reacting in their own ways? Or is the reaction to damage marshaled by a few controlling systems at the top level, leading to a sea of complexity downstream of those controlling systems? Which of these is the case makes a big difference as to the type of potential rejuvenation therapies that might be useful to attempt – though in either case repairing the damage sounds like a better idea to me.

Here, we measure changes in the transcriptome, histone modifications, and DNA methylome in three metabolic tissues of adult and aged mice. Our main question was whether common regulatory players underlie the seemingly tissue- and species-specific molecular footprint of aging. We show that although the molecular footprint of aging evolves differently across tissues, striking similarities emerge in terms of affected pathways and underlying regulators. For instance, the liver’s aging footprint is dominated by changes in transcriptome and DNA methylome. In contrast, transcriptomes of heart and quadriceps are relatively stable but have marked changes in histone modification profiles around genes. Despite all these differences, similar pathways are affected in these distinct layers.

The striking similarity in transcription factor (TF) enrichment between different mouse and human tissues implies that there may be a common and perhaps restricted set of TFs underlying the aging footprint across tissues and species. The ZIC1 motif is highly enriched across multiple tissues and gene-regulatory layers. ZIC1 increases with age in many peripheral human tissues. Although its relationship or possible implication in aging has not been studied extensively, it has been shown that its brown adipose tissue (BAT) expression increases with age and body mass index, concurrently with a decrease in BAT activity. In addition, ZIC1 and ZIC2 transactivate apolipoprotein E (APOE) expression, one of the strongest human longevity determinants. The facts that APOE increases with age and that higher APOE levels correlate with negative outcomes in age-related diseases such as Alzheimer’s disease render ZIC1 a prime candidate driver of gene regulatory changes associated with aging.

We also identify other TFs, such as HMGA1, TBP, and CXXC1, as candidate regulators of the aging process. HMGA1 has been linked to mitochondrial function, repair, and maintenance and is implicated in promoting senescence-associated heterochromatic foci, which are associated with transcriptional repression. In addition, it has recently been shown to promote the senescence-associated secretory phenotype (SASP) through its effect on NAD+ metabolism. The TATA box binding protein (TBP) motif is enriched in genes that decrease with age. Although this TF has not been directly linked to aging, it can harbor variations in polyglutamine repeats, which may be relevant in age-related processes such as neuro-muscular degenerative disease. CXXC1, or Cfp1, is a member of the Setd1 H3K4 methyltransferase complex and binds non-methylated DNA of transcriptionally permissive promoters. Given the trend for hypermethylation with age, CXXC1 binding to many promoters may be affected, which may lead to differences in H3K4 methylation. CXXC1 may therefore be an important link between the different molecular layers, which merits further mechanistic investigation, especially given that its motif’s enrichment varies in direction in different tissues, suggesting a complex context-dependent relationship with aging.

Incorporating Microelectronics into Bioartificial Blood Vessels

Researchers here report on an interesting proof of concept, incorporating electronic device capabilities into the flexible biomaterials used as scaffolding for blood vessel tissue engineering. As a next generation technology to potentially replace the use of stents in the treatment of cardiovascular disease, bioartificial blood vessel sections are already promising. Adding to this the programmable ability to alter nearby cell behavior, control delivery of gene-based therapeutics, or report sensory data on cells and blood flow opens up intriguing new vistas for the future.

A variety of tissue-engineered blood vessels (TEBVs) have been created to provide mechanical support for hard-to-treat blockages of tiny blood vessels, but these have limitations, and none “has met the demands of treating cardiovascular diseases. We take the natural blood vessel-mimicking structure and go beyond it by integrating more comprehensive electrical functions that are able to provide further treatments, such as gene therapy and electrical stimulation.”

Researchers fabricated a new form of electronic blood vessels using a cylindrical rod to roll up a membrane made from poly(L-lactide-co-ε-caprolactone). In the lab, they showed that electrical stimulation from the blood vessels increased the proliferation and migration of endothelial cells in a wound-healing model, suggesting that electrical stimulation could facilitate the formation of new endothelial blood vessel tissue. They also integrated the flexible circuitry with an electroporation device, which applies an electrical field to make cell membranes more permeable, and observed that this successfully delivered green fluorescent protein DNA into three kinds of blood vessel cells.

A three-month trial in rabbits showed, they say, that the artificial arteries appeared to function just as well as natural ones, with no sign of narrowing, and with no inflammatory response in the host. Part of the next stage is to try to pair the electronic blood vessels with smaller electronics than the electroporation device used in this study.