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- Senescent Cells Accelerate the Accumulation of More Senescent Cells
- Today is Giving Tuesday: Help Us to Expand SENS Research Foundation Programs to Create New Rejuvenation Therapies
- News from the Methuselah Foundation: Support this Organization to See More Such Progress in the Future
- What Else can be Achieved with Better Control of Senescent Cells?
- Why do Women Experience Worse Health than Men in Late Life?
- Don't Wait for Aging to be Classified as a Disease
- Evidence for Cellular Senescence to Contribute to Retinal Degeneration
- Mitochondrial Decline Correlates with Onset of Sarcopenia in Nematodes
- Arguing for Autophagy as the Primary Mechanism by which Exercise and Calorie Restriction Improve Health and Longevity
- A DNA Methylation Signature is Shared Between Calorie Restriction, mTOR Inhibition, and Growth Hormone Inhibition
- Even Eliminating the Top Four Causes of Age-Related Death Gains Few Years of Life
- Further Evidence for Cancer Treatments to Accelerate Aging
- Dysfunctional Autophagy in an Alzheimer's Disease Model Unexpectedly Results in Lower Levels of Amyloid-β
- The Purpose of Longevity
- RNA Fragments and Ribosomal Failure as a Consequence of Oxidative Stress
Senescent Cells Accelerate the Accumulation of More Senescent Cells
Aging is an accelerating process, in which new symptoms of degeneration appear ever faster as the decline progresses. This is characteristic of the aging of any complex system, in that damage to component parts - and the dysfunction that results - tends to produce further damage and dysfunction. To pick one example of many in human biochemistry, cross-linking in the extracellular matrix causes stiffening of blood vessels, which in turn causes hypertension, which in turn causes pressure damage to delicate tissues. Or accumulation of amyloid-β in the brain leads to accumulation of tau that in turn causes cell death and dementia. Thousands of such chains of cause and effect can be found in human aging, few of which are catalogued end to end and in all their detail. The roots of aging and the causes of mortality at the ends of aging are fairly well mapped, but the complexity in between is still a matter of a few paths through a dark forest.
The lack of understanding of the details of the progression of aging, how metabolism is disrupted, and how and why that produces the next form of damage and dysfunction in the chain of cause and consequence, is one of the reasons why it is a slow and expensive process to attempt to alter metabolism to be more resilient. That is true even given the easily established altered states of metabolism, such as that produced by calorie restriction, in which aging is modestly slowed. Metabolism is ferociously complex and incompletely understood. It is thus better to focus on the causes of aging, those forms of damage that arise in the normal operation of youthful metabolism, and are simply side-effects of that operation. If those initial, root cause forms of damage can be prevented or periodically repaired, then it doesn't much matter how they go on to cause aging.
The accumulation of senescent cells is one of the root causes of aging. Even if there were no other causes of aging, cellular senescence would still kill us given time. Senescent cells are constantly created when cells reach the Hayflick limit, or suffer mutational damage, or are exposed to other excessive stresses. Near all self-destruct, and near all that fail in that are instead destroyed by the immune system. A tiny minority remain, to generate a potent mix of signals known as the senescence-associated secretory phenotype. This generates chronic inflammation, disrupts the nearby structure of tissues, and, perhaps worse of all, encourages other cells to become senescent as well. This latter behavior makes sense given the tasks that senescent cells have evolved to carry out, meaning suppression of cancer by preventing at-risk cells from replicating further, steering embryonic growth, and regeneration of injuries, but it also makes their contribution to aging that much worse.
Cellular senescence is thus its own self-contained accelerating process of aging. The more senescent cells present in tissue, the more likely it is that other cells will become senescent in response to stresses or damage. This is yet another reason to prioritize the distribution and further development of safe and effective senolytic therapies capable of selectively destroying senescent cells. These errant cells are in effect actively maintaining a state of age-related dysfunction through their signaling. Removing them is a form of rejuvenation, demonstrated in animal studies, and in the process of being further demonstrated in human clinical trials.
The bystander effect contributes to the accumulation of senescent cells in vivo
Senescent cells accumulate in many tissues during aging. Genetic or drug-mediated specific ablation of senescent cells ameliorates a wide range of age-associated disabilities and diseases in mice. Cell senescence can be triggered by replicative exhaustion or stressors, specifically oncogenic and DNA-damaging stress. Moreover, pre-existing senescent cells in vitro are capable of inducing a senescent phenotype in surrounding bystander cells via integrated ROS- and NF-κB-dependent signalling pathways. It has been suggested that this senescence-induced bystander senescence might be a relevant trigger of senescent cell accumulation in vivo, based on focal clustering of senescent cells in old mouse livers and of SASP-mediated accumulation of senescent cells around pre-neoplastic lesions.
In accordance, autologous transplantation of senescent fibroblasts into healthy knee joints resulted in the development of an osteoarthritis-like condition in mice. Very recently, it was shown that intraperitoneal transplantation of relatively low numbers of senescent cells caused persistent physical dysfunction in mice, indicating that senescent cells can induce a deleterious bystander effect in vivo. However, direct evidence that transplanted or pre-existing senescent cells do induce senescence in surrounding tissues is still weak.
The impact of cell senescence for aging of skeletal muscle and the dermal layer of the skin has been questioned because the major cell types are slowly dividing (dermal fibroblasts) or not dividing at all (myofibres). However, the DNA damage response (DDR) induces a senescence-like phenotype in postmitotic cells like neurons or retinal cells. In the dermis, accumulation of fibroblasts with telomere dysfunction and other senescence markers has been observed in different mammalian species. In mouse skeletal (gastrocnemius) muscle, expression of various senescence markers increased with age and decreased after selective ablation of p16-expressing presumably senescent cells.
After observing increased frequencies of multiple senescence markers in aging myofibres, we xenotransplanted small numbers of senescent human fibroblasts into mouse skeletal muscle and skin. Bioluminescent and fluorescent labelling enabled tracking of the injected cells in vivo for at least 3 weeks as well as their identification in cryosections in situ. We found that mouse cells surrounding the injection sites showed increased frequencies of multiple senescence markers when senescent cells (but not non-senescent cells) were xenotransplanted. Comparing senescent cell accumulation rates in normal and immunocompromised mice under either ad libitum feeding or dietary restriction enabled separate estimations of bystander-dependent versus cell-autonomous senescent cell accumulation, indicating a significant and possibly major contribution of the bystander effect. Adjacent to injected senescent cells, the magnitude of the bystander effect was similar to the increase in senescence markers in myofibres between 8 and 32 months of age.
Today is Giving Tuesday: Help Us to Expand SENS Research Foundation Programs to Create New Rejuvenation Therapies
Today is Giving Tuesday, a day on which to ponder the change you wish to see in the world, and then help to make it a reality. For my part, I would prefer that no-one had to suffer and die because of the damage that accumulates in all of our bodies, through no fault of our own. Being born should not be accompanied by the guarantee of a slow, troubled, and painful decline and death, as it is today. We can do better than this limited human condition we find ourselves in. We can dig ourselves out of this pit. We can develop the means to repair the cell and tissue damage that causes aging, and build a world in which being old doesn't mean being diminished, sick, and at risk of imminent death.
The SENS Research Foundation tackles the lines of scientific development that are required for the first rejuvenation therapies to reach the clinic. The foundation staff unblock the work that has become stuck due to lack of tools, fund the work that has languished due to lack of interest from mainstream, highly conservative funding organizations, and tirelessly persuade the research community to take rejuvenation seriously. They and their allies, such as the Methuselah Foundation, have changed the face of aging research. They continue to produce results, and everything they have done has been powered by charitable donations, but the everyday philanthropy of people like you and I. To see this continue, we must continue to offer our material support.
Every one-time donation made today will be matched, and everyone who signs up as a monthly donor to the SENS Research Foundation will have the next year of their donations matched from the 54,000 SENS Patron challenge fund put up by Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! We believe in the value of the work done by the SENS Research Foundation, and want you to join us in supporting that work.
We, all of us, are the first people to be offered this chance. We are the first to be alive at a time in which medical biotechnology has advanced to the point at which rejuvenation is a practical, real, near term possibility. Every capable individual in the world should be leaping at the chance to fund this research and development. But the sad truth of the matter is that if you are reading this, then you are in a tiny minority. The vast majority of people have no idea that a revolution in health and aging could be just around the corner, if only given support and funding. They believe that the rest of their lives will look the same as those of their grandparents, that aging is set in stone and cannot be changed, that they will suffer and die on a schedule.
Without funding, without publicity, without large-scale development programs, that might even become true for our generation - there are no guarantees in development. Technologies do not become widespread just because they are possible; the realization of progress requires deliberate effort and a great deal of persuasion. Someone has to step up and sound the bell, to shine the lantern. Someone has to be first to tell their friends that rejuvenation therapies are nearly here, given funding. Someone has to take the step of making a charitable donation to help run research programs, rather than just hoping for a better future. If not you, one of the minority reading this missive, then who?
News from the Methuselah Foundation: Support this Organization to See More Such Progress in the Future
The Methuselah Foundation is one of the most important non-profits in our longevity science community. It was the original home of the first SENS rejuvenation research programs, and has used our philanthropic support to fund a range of important projects and startups. If you look at many of the advances and initiatives of the past twenty years in our community, behind the scenes you'll find that Methuselah Foundation CEO Dave Gobel was in some way involved. All communities are the sum of their connections, and at the center of ours you will find the Methuselah Foundation and the SENS Research Foundation that it gave rise to, as our community grew in size and scope.
Below find the latest update from the Methuselah Foundation on their progress in helping to cultivate an industry of startups to produce therapies to treat aging, and in advancing the state of tissue engineering for the creation of new organs. Many of us in the community have supported the Methuselah Foundation from the early days, from the days in which the Methuselah 300 was established, a group of people who pledged to donate 25,000 over a decade. There are still spaces for those who want to support an organization that truly makes a difference. Give it some thought.
What If You Could Turn Back The Clock At A Cellular Level?
Enter Turn Biotechnologies, a company we began supporting in August after meeting them in California in February. Turn Bio is on a clear mission: to extend the health span by reverting cellular age. By doing that, tissues and organs can rejuvenate so that the whole body can be healthier and live longer. To do this, Turn Bio developed a technology capable of safely reprogramming how the DNA functions epigenetically. This approach effectively returns cells to a younger state, improving their function without changing their identity. The team comes out from Stanford University and is comprised of the proven scientists Vittorio Sebastiano, Marco Quarta, and Jay Sakar. The new CEO, Gary Hudson, is well known to many of us. The scientific team is optimizing the therapy and will be looking for strategic partnerships soon. As you might have realized by now, this activity falls under two of our six mission strategies: Debug the Code and Restock the Shelves.
New Parts for People: Progress on 3D Bioprinting of Organs
Many of you know Methuselah has been able to fully develop the mission strategy of New Parts for People. With our Support of Organovo, Organ Preservation Alliance, and New Organ Alliance, we are happy to have helped create an environment that fosters innovation in the printing of 3D tissues. We know that the organ shortage will be a thing of the past once these technologies fully mature. Our desire to accelerate results has moved us to make progress in two needle-moving activities.
First, we held a Vascular Tissue Challenge at NASA Ames this past March to continue the road mapping efforts to solve the vascularity challenge. As you may know, while full organs can be 3D printed, lack of blood perfusion is a roadblock to their practical use. In other words, the 3D printed organs begin to die almost as quickly as they are being printed. We partnered up with NASA to create a sizeable prize that would entice world-class teams to join in solving this problem. We are happy to say that 13 teams from academia and the private sector are nearing the point of submission for winning the prize.
We also decided to support a new venture called Volumetric. This team is focused on facilitating 3D printed organs for us all. They are doing this by producing biomaterials that will be used as inks in stereolithographic bioprinting. They just graduated from the NSF I-Corps program designed to help academics translate their breakthroughs into products. In just a few weeks, they have been able to partner up with top 3D bioprinting companies and have started focusing on the production of a bioprinter. What is so exciting about this bioprinter is that it will allow far more academics around the world to own a 3D printer due to its significantly reduced expense compared with alternatives in the market. We think that this move will keep democratizing research in this sector, which will accelerate results.
Methuselah Fund Successfully Closes Its Founder's Round!
We are happy to declare victory as the M Fund is finally closed! As everyone knows, a sector becomes legitimized once investors are excited to put the money in it. We understand that enticing money beyond the research budgets is vital to accelerating results. We wholeheartedly believe in the translation of science to the clinic and know that companies are obligated to do so by coming up with products. That is why the M Fund is so vital to making 90 the new 50 by 2030. With the help of some of you, we successfully finished this Founder's round and raised the full amount we were after. The M Fund investigates several companies weekly, looking for the best ventures to support. We hope to keep pouring fire into this nascent investment sector.
Study: What does it mean to be 90 vs 50 years-old?
What defines an average 90-year-old scientifically? What defines a 50-year-old? How could we make 90 the new 50 by 2030? Clearly, this is something that was of paramount importance since we decided to have the self-imposed deadline of year 2030. We know it is important to understand these questions in order to find out if we succeeded or not by the time 2030 comes around. Since the M Fund has been created to accelerate results in this field by means of targeted investments, we decided early on to study hundreds of longevity-related papers to come up with answers that could point us that way. The study yielded the added benefits of giving us a significant advantage in understanding the investable science that is on the horizon, and is available at our website. We know that you will find this extremely interesting and hope it can add value to your lifestyle and direct investment goals.
What Else can be Achieved with Better Control of Senescent Cells?
At the present time, the main focus of therapeutic development involving senescent cells is the safe, selective destruction of as many such cells as possible. The accumulation of senescent cells is an important cause of aging and age-related pathology, and removing even just a quarter or a half of them - and in only some organs and tissues - has been shown to significantly extend life and improve health in mice. The first human trials are underway and the results will be published over the next year or so.
While senescent cells do a good job of accelerating our demise, it is undeniably the case that these cells also serve quite useful purposes for a short time after their creation. They exist for a reason, and the problem is not their existence per se, but that they are not removed efficiently enough after the job of the moment is accomplished. Senescence cells secrete a potent mix of signals that is well adapted for those tasks, but if allowed to continue for the long term, this signaling is highly disruptive of tissue structure and organ function.
Cellular senescence as a process serves to help define the shape of tissues during embryonic development, but in adult life its primary positive roles involve suppression of cancer and guidance of wound healing. Since cells become senescent in response to damage, such as the mutational damage to DNA that can lead to cancer, countless potential cancers are avoided because the cells involved enter a senescent state in which they can no longer replicate. They then rouse the interest of the immune system via inflammatory signaling, to ensure destruction. In the case of wound healing, the signal molecules secreted by senescent cell encourage the activities needed for regrowth and restructuring.
In a near future in which senescent cells can be very efficiently destroyed, then it becomes possible to think about delivering senescent cells to patients, or selectively forcing patient cells into a senescent state. This could have applications in the treatment of cancer, in which provoking cancerous cells into senescence has long been a desirable goal for chemotherapy, or in acceleration of wound healing, for example. After the job is done, efficient senolytic therapies could be delivered to remove the senescent cells, preventing them from causing long-term harm to the patient.
Senescent cells: A new Achilles' heel to exploit for cancer medicine?
In response to various intrinsic and/or extrinsic stimuli, cells enter an essentially irreversible senescent state. Senescent cells are frequently implicated in multiple disorders, mainly through secretion of numerous bioactive molecules, a distinctive phenomenon found a decade ago and termed as the senescence-associated secretory phenotype (SASP). The full SASP spectrum comprises a myriad of soluble factors including pro-inflammatory cytokines, chemokines, growth factors, and proteases, whose functional involvement can be classified into several aspects including but not limited to extracellular matrix formation, metabolic processes, ox-redox events, and gene expression regulation. The SASP promotes embryonic development, tissue repair, and wound healing, serving as an evolutionarily adapted mechanism in maintaining tissue and/or organ homeostasis.
Although the SASP is beneficial to several health-associated events, more evidence has showed that it actively contributes to the formation of a pro-carcinogenic tumor microenvironment. Long-term secretion of the SASP factors by senescent cells can impair the functional integrity of adjacent normal cells in the local tissue, serving as a major cause of chronic inflammation which drives aging-related degeneration of multiple organs. Thus, senescent cells and their unique phenotype, the SASP, can be defined as a form of antagonistic pleiotropy, a property that is beneficial in early life and during tissue turnover, but deleterious over time with advanced age.
A new function of the SASP was recently discovered, which is linked with increased expression of stem cell markers and keratinocyte plasticity upon short term exposure of cells to the SASP in vitro and liver regeneration in vivo, thus raising the possibility that transient therapeutic delivery of senescent cells could be harnessed to promote tissue regeneration.
Interestingly, a study of spontaneous escape from cellular senescence found that cells released from senescence can re-enter the cell cycle with pronouncedly enhanced stemness and Wnt-dependent growth potential. Thus, senescence-associated reprogramming promotes cancer stemness (senescence-associated stemness, or SAS), a distinct property that has profound implications for cancer therapy and presents new mechanistic insights into cancer cell plasticity. Partially resembling cancer cells which pose substantial threat to human lifespan, senescent cells are functionally involved in tumor progression and can be viable targets for some reasons. Fortunately, senescent cells share common biochemical features, allowing use of a single therapeutic agent to eliminate them from the tissue microenvironment. Given that many chemotherapeutics induce collateral senescence, pharmaceutical agents targeting senescent cells can be a key component of advanced anticancer arsenal.
Why do Women Experience Worse Health than Men in Late Life?
It is well known that females of many species live longer than males. Some fundamental aspects of gender roles in mating and reproduction tend to lead to this outcome. It isn't peculiar to our species, so it can't have anything to do with technology or the sociology that comes with intelligence. Thus the dominant arguments really have to be evolutionary in nature. It is less well known that, in our species at least, women have worse health than men in later life, despite a greater life expectancy. This also probably arises at root from fundamental aspects of gender roles, but there is a great deal of room to argue for any specific position on how exactly it is that evolutionary processes lead to the observed result.
In the paper noted here, researchers take a swing at explaining how we could arrive at the position of worse female health, invoking the selection of gene variants that benefit males in late life but harm females in late life. This is a sort of cross-gender antagonistic pleiotropy to complement the usual understanding of how genetic variants that harm individuals in later life might arise. The size of the effect may depend upon the existence of menopause, which is only observed in a few species, however, which makes it harder to support any theoretic position with solid data. The paper makes for interesting reading, as is the case for most such research.
That said, I disagree with the authors' assertion that we need to understand this and other similarly subtle evolutionary mechanisms in order to produce greater human longevity. Understanding is not a bad thing, mind, and science is a worthy goal, but here understanding is near completely orthogonal to progress in the treatment of aging as a medical condition. Both men and women age for same underlying reasons, the accumulation of molecular damage is the same in both genders. After the research and medical communities have built therapies that can repair that damage, then it won't matter in the slightest how evolution has handled or mishandled late life resilience to high levels of damage. No-one will have high levels of cell and tissue damage any more.
Study reveals why older women are less healthy than older men
Scientists have long wondered why older women are less healthy than older men, given that men at any given age are more likely to die than women (a puzzle known as the "male-female, health-survival paradox"). The answer, according to recent research, is "intralocus sexual conflict" - genes that benefit one sex but harm the other. The researchers used mathematical models and experimental data on flies to show that such genes can easily spread if they take effect after female reproduction stops.
"Shared genes tether the sexes together in an evolutionary tug of war. Selection is trying to push females and males in different directions, but the shared genome means each sex stops the other from reaching its optima. Basically, certain genes will make a good male but a bad female, and vice versa. However, after females reaches menopause, they no longer reproduce to pass on their genes which means selection (which is reproduction) on females is greatly weakened. So after that point, any genes that improve late-life male fitness will accumulate, even if they harm female fitness."
Intralocus sexual conflict can resolve the male-female health-survival paradox
While we broadly understand why mortality risk rises as fertility and general performance decline with age, it is less clear why the tempo and severity of these changes often differ between the sexes. In humans, survival, fertility, and performance show sex-specific patterns of decline with age. Strikingly, women stop reproducing decades before dying, while men can reproduce throughout their adult lives. Additionally, men are more likely to die than women in most age-classes, but are healthier than women late-in-life. To be clear, this is not just due to the selective loss of low quality males, as female mortality rates are lower than male rates at nearly all ages despite poorer female health. This sex difference has been termed the "male-female, health-survival paradox", and while its causes are not well understood, some resolution of it is needed if we are to ensure healthy aging as human lifespan increases.
Here we focus on the health aspect of the paradox and suggest that intralocus sexual conflict might explain why women are less healthy than men late-in-life. Intralocus sexual conflict occurs when the sexes have different optimal values for a shared trait with a common genetic basis. For example, male broad-horned flour beetles develop enlarged mandibles and males with larger mandibles have higher fitness. However, daughters of males with large mandibles have lower fitness because of the masculinisation of the body that occurs with these genotypes. This means that alleles associated with mandibles are subjected to an intersexual tug-of-war over optimal values, with high fitness male genotypes making low fitness females. This type of conflict means that the alleles encoding a high-quality male often produce low quality females and vice versa.
For intralocus sexual conflict to explain the health-survival paradox, male-benefit sexually antagonistic alleles with late-acting effects must accumulate. This is entirely feasible because women experience the menopause. This means that selection against any alleles with costly effects when expressed in females will weaken dramatically once women undergo the menopause and stop reproducing, because these alleles can only have indirect effects on female fitness. However, in men there will be selection for male-benefit alleles over the entire lifespan because men can keep reproducing until advanced ages. This would allow late-acting, male-benefit sexually antagonistic alleles to spread and accumulate in the human genome and reduce female health late-in-life, as females carrying late-acting male-benefit alleles express trait values closer to male than female optima.
To formally test this hypothesis, we assessed whether a male-benefit, sexually antagonistic allele could spread through a diploid population using an evolutionary modelling framework. We show theoretically that under biologically realistic assumptions of costs and benefits, such antagonistic alleles can accumulate. Using Drosophila model systems, we then assessed whether sexual conflict solutions are feasible by testing whether populations evolving with selection for late-life male reproduction, but with no direct selection on females (as is the case for post-menopausal women), developed late-life costs to females. Our data broadly support the predictions and suggest that intralocus sexual conflict could help explain the male-female, health-survival paradox.
Don't Wait for Aging to be Classified as a Disease
The author of this open access commentary has long been a strong proponent of forms of programmed aging theory, as well as an outspoken advocate for mTOR inhibitors as an approach to treating aging. I don't agree with programmed aging, and I think mTOR inhibition - like all approaches to modestly slowing aging by mimicking calorie restriction - is of too little benefit to merit large-scale expenditure of research and development resources. The scientific and biotechnology communities should be able to do far better via the SENS-style approaches based on damage repair, and indeed that point is already being demonstrated in the case of senolytic therapies. This article, however, is more of a commentary on high level strategy and the effects of regulation, coupled with a desire to forge ahead rather than hold back in the matter of treating aging, thus I concur with much more of what is said than is usually the case.
For decades, one of the most debated questions in gerontology was whether aging is a disease or the norm. At present, excellent reasoning suggests aging should be defined as a disease - indeed, aging has been referred to as "normal disease." Aging is the sum of all age-related diseases and this sum is the best biomarker of aging. Aging and its diseases are inseparable, as these diseases are manifestations of aging.
What then is aging without diseases, so called "healthy" aging. "Healthy" aging has been called subclinical aging, slow aging, or decelerated aging, during which diseases are at the pre-disease or even pre-pre-disease stage. Diseases will spring up eventually. "Healthy" aging is a pre-disease state in which asymptomatic abnormalities have not yet reached the artificial definitions of diseases such as hypertension or diabetes. Instead of healthy aging, we could use the terms pre-disease aging or decelerated aging.
Currently, the term healthspan lacks clarity and precision especially in animals. Although the duration of healthspan depends on arbitrary criteria and subjective self-rating, it is a useful abstraction. In theory, a treatment that slows aging increases both healthspan (subclinical period) and lifespan, whereas a treatment that increases lifespan (e.g., coronary bypass, defibrillation) is not necessarily increase healthspan. The goal of both anti-aging therapies and preventive medicine is to extend healthspan (by preventing diseases), thus extending total lifespan.
The fact that aging is an obligatory part of the life of all organisms is not important. What is important is that aging is deadly and, most importantly, treatable. Consider an analogy. Is facial hair in males a disease? No of course, not. Still most men shave it, effectively "treating" this non-disease, simply because it is easily treatable. Is presbyopia (blurred near vision) a disease? It occurs in everyone by the age of 50 and is a continuation of developmental trends in the eye. It is treated as a disease because it is easily treatable with eye glasses. Unlike presbyopia, menopause in females is not usually treated because it is not easy to treat. Thus, the decision to treat or not to treat is often determined by whether it is possible to treat. It does not matter whether or not the target of treatment is called a disease.
It is commonly argued that aging should be defined as a disease so as to accelerate development of anti-aging therapies. This attitude is self-defeating because it allows us to postpone development of anti-aging therapies until aging is pronounced a disease by regulatory bodies, which will not happen soon. Aging does not need to be defined as a disease to be treated. Anti-aging drugs such as rapamycin delay age-related diseases. If a drug does not delay progression of at least one age-related disease, it cannot possibly be considered as an anti-aging drug, because it will not extend life-span by definition (animals die from age-related diseases).
Evidence for Cellular Senescence to Contribute to Retinal Degeneration
Forms of retinal degeneration are commonplace in later life, leading to progressive and presently irreversible blindness - though there are promising human trial results emerging from the tissue engineering community of late. The accumulation of senescent cells is a feature of aging found in all tissues. These errant cells should self-destruct or be destroyed by the immune system, but enough survive to linger and cause problems. They secrete an inflammatory mix of signals that disrupts normal tissue structure and function, and their presence is one of the root causes of aging. Thus it is not surprising to find evidence for senescent cells to contribute to retinal degeneration, such as that presented here.
It is good news for patients, and everyone else, whenever cellular senescence is associated with the progression of yet another age-related condition. Low-cost senolytic drugs capable of removing a significant fraction of senescent cells already exist, and numerous companies are working on the commercial development of further and better options. To the degree that we can all access senolytic treatments, and to the degree that those treatments are efficient in removing unwanted senescent cells, then we will age more slowly and the onset of age-related diseases will be postponed.
Regenerative medicine approaches based on mesenchymal stem cells (MSCs) are being investigated to treat several aging-associated diseases, including age-related macular degeneration (AMD). Loss of retinal pigment epithelium (RPE) cells occurs early in AMD, and their transplant has the potential to slow disease progression. The human RPE contains a subpopulation of cells - adult RPE stem cells (RPESCs) - that are capable of self-renewal and of differentiating into RPE cells in vitro. However, age-related MSC changes involve loss of function and acquisition of a senescence-associated secretory phenotype (SASP), which can contribute to the maintenance of a chronic state of low-grade inflammation in tissues and organs.
In a previous study we isolated, characterized, and differentiated RPESCs. Here, we induced replicative senescence in RPESCs and tested their acquisition of the senescence phenotype and the SASP as well as the differentiation ability of young and senescent RPESCs. Senescent RPESCs showed a significantly reduced proliferation ability, high senescence-associated β-galactosidase activity, and SASP acquisition. RPE-specific genes were downregulated and p21 and p53 protein expression was upregulated. Altogether, the present findings indicate that RPESCs can undergo replicative senescence, which affects their proliferation and differentiation ability. In addition, senescent RPESCs acquired the SASP, which probably compounds the inflammatory RPE microenvironment during AMD development and progression.
Mitochondrial Decline Correlates with Onset of Sarcopenia in Nematodes
Researchers here demonstrate an association between reduced mitochondrial function and onset of sarcopenia in nematode worms. Muscle tissue requires a lot of energy for function and maintenance, and that energy is supplied in the form of adenosine triphosphate (ATP) by the roving herds of mitochondria found within muscle cells. Progressive failure of mitochondrial function is a feature of aging, and is thought to be a contributing cause of the loss of muscle mass and strength, known as sarcopenia, that is characteristic of late life physiology.
Sarcopenia is not exclusive to humans, and has been observed in non-human primates, dogs, rodents, and even the microscopic worm, C. elegans. These observations, therefore, suggest that sarcopenia is an evolutionarily conserved process and whilst some evidence suggests the underlying mechanisms might also be conserved, it remains an open question. There are several theories regarding the cause of sarcopenia, but we do not yet fully understand its aetiology, not least because of an absence of life-long, prospective studies.
Muscle architecture is highly conserved between C. elegans and mammals and the major signaling pathways and degradation systems are also present in both system. Thus, C. elegans is a good organism in which to investigate the molecular changes to muscle with ageing. Previous studies have shown that ageing in C. elegans muscle is characterized by altered structure and reduced function. This is displayed as progressive disorganization of sarcomeres and reduced cell size. Alterations to sarcomere structure have been associated with changes to locomotive ability. Alongside changes to muscle structure and function, mitochondrial defects such as increased fragmentation and reduced mitochondrial volume have also been observed in the body wall muscles of aged C. elegans.
Recently large scale studies using RNAi have been conducted to investigate how muscle health is maintained in C. elegans. These studies have examined the effect of knocking down more than 850 genes on sub-cellular muscle architecture. The results highlighted that in control animals sub-cellular components remained normal through early adulthood, however, after day three of adulthood, abnormal sarcomere and mitochondrial structures were observed. Furthermore, mitochondrial fragmentation appeared to arise earlier in the ageing process than the alterations to sarcomere structure. These data suggest that mitochondrial abnormalities precede other changes to muscles with age.
Here, we use C. elegans natural scaling of lifespan in response to temperature to examine the relationship between mitochondrial content, mitochondrial function, and sarcopenia. Mitochondrial content and maximal mitochondrial ATP production rates (MAPR) display an inverse relationship to lifespan, while onset of MAPR decline displays a direct relationship. Muscle mitochondrial structure, sarcomere structure, and movement decline also display a direct relationship with longevity. Notably, the decline in mitochondrial network structure occurs earlier than sarcomere decline, and correlates more strongly with loss of movement, and scales with lifespan. These results suggest that mitochondrial function is critical in the ageing process and more robustly explains the onset and progression of sarcopenia than loss of sarcomere structure.
Arguing for Autophagy as the Primary Mechanism by which Exercise and Calorie Restriction Improve Health and Longevity
Autophagy is the name given to a collection of maintenance and recycling mechanisms responsible for removing damaged and unwanted proteins and structures from within cells. Many of the means of modestly slowing aging demonstrated in laboratory species feature increased levels of autophagy, in in some cases that increase in autophagy has been shown to be necessary for benefits to result. That autophagy is the most important means by which beneficial stresses such as exercise and calorie restriction improve health and longevity is by no means a novel argument. It has been made for decades, with increasing confidence.
Despite this, there has been comparatively little progress when it comes to the development of therapies that directly target the operation of autophagy, as opposed to calorie restriction mimetics that do so indirectly by targeting regulators known to be involved in the calorie restriction response. (We could argue about which side of that line mTOR inhibitors fall on, but their connection to aging arose out of work on calorie restriction rather than work on autophagy per se). In part this is because safely manipulating the state of metabolism is very challenging; metabolism is enormously complex and still comparatively poorly mapped.
Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age-related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidence suggests that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality.
Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy-dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise-induced TORC1 and autophagy signaling share common pathways with that of CR.
Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity.
A DNA Methylation Signature is Shared Between Calorie Restriction, mTOR Inhibition, and Growth Hormone Inhibition
Calorie restriction, mTOR inhibition, and blockade of growth hormone interaction with its receptor all result in slowed aging and extension of healthy life span in mice. These interventions beneficially alter the operation of metabolism in humans, but do not enhance human life span to anywhere near the same degree; the current consensus suggests that an additional five years is probably the largest effect that could be expected to exist. The mechanisms involved overlap, and nutrient sensing plays an important role. Thus researchers looking for common epigenetic signatures shared by all of these interventions have found such shared signatures.
Long ago, the earliest organisms evolved to better maintain themselves in response to seasonal famine, extending their lives and raising the odds of successful reproduction later. That ability has been passed down over evolutionary time, and is present in near all species tested to date. The shorter the species life span, the greater the relative extension of life needed to pass through a season of famine. Thus mice that live only a couple of years can extend their lives by as much as 40% via stress triggers such as limited nutrient intake, while humans with a life span of decades do not exhibit a significant extension of life in this circumstance. Much of the same cellular machinery exists in both species, however, explaining why humans can obtain health benefits from the practice of calorie restriction.
Dietary, pharmacological, and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored.
We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation, and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation.
By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.
Even Eliminating the Top Four Causes of Age-Related Death Gains Few Years of Life
Aging is a general process of deterioration, and any specific age-related disease, even one of the fatal conditions, is only a very narrow manifestation of that broad deterioration. It is a fantasy to think that any one specific age-related condition can be cured, entirely removed from the full spectrum of damage that is aging, in isolation, and without impact to the rest of aging. The only way to cure an age-related condition is to repair all of the forms of cell and tissue damage that cause it, and each type of damage has widespread effects beyond its contribution to any one named disease. Aging is treated all at once, or not at all, and is treated by addressing the root causes rather than the late disease state, in other words.
This explains how one can arrive at the results of the study noted here. Run the numbers on age-related mortality, remove the contribution of the few top causes of death, and the result is that life is extended by very little. Aged people will shortly die from other causes, given a hypothetical, fantastical way of absolutely preventing mortality attributed to one specific age-related disease in isolation of all of the others.
In the real world, there are ways of affecting, say, cardiovascular mortality to some degree while affecting the progression of other forms of mortality to a lesser degree: statins and antihypertensive medications, for example. But this is isn't the same thing. The reduction of specific forms of downstream damage (atherosclerotic lesions or high blood pressure) causes benefits to mortality that are spread across many age-related conditions, and are thus larger than the numbers in the study here. This is the way that the first rejuvenation therapies will also work, except that they will produce far greater benefits.
To curb the rising global burden of non-communicable diseases (NCDs), the UN Sustainable Development Goals (SDGs) include a target to reduce premature mortality from NCDs by a third by 2030. We estimated age-specific mortality in 183 countries in 2015, for the four major NCDs (cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes) and all NCDs combined, using data from WHO Global Health Estimates. We then estimated the potential gains in average expected years lived between 30 and 70 years of age (LE30-70) by eliminating all or a third of premature mortality from specific causes of death in countries grouped by World Bank income groups. The feasibility of reducing mortality to the targeted level over 15 years was also assessed on the basis of historical mortality trends from 2000 to 2015.
Reducing a third of premature mortality from NCDs over 15 years is feasible in high-income and upper-middle-income countries, but remains challenging in countries with lower income levels. National longevity will improve if this target is met, corresponding to an average gain in LE30-70 of 0.64 years worldwide from reduced premature mortality for the four major NCDs and 0.80 years for all NCDs. According to major NCD type, the largest gains attributable to cardiovascular diseases would be in lower-middle-income countries (a gain of 0.45 years), whereas gains attributable to cancer would be in low-income countries (0.33 years). Eliminating all deaths from the four major NCDs could increase LE30-70 by an average of 1.78 years worldwide, with the greatest increases in low-income and lower-middle-income countries. On average, eliminating deaths from all NCDs (compared with estimates for only the four major types) would lead to a further 25% increase in the gains in LE30-70.
Further Evidence for Cancer Treatments to Accelerate Aging
People who have undergone chemotherapy or radiotherapy suffer a reduced life expectancy and increased risk of suffering other age-related conditions even when the cancer is defeated. These cancer therapies produce large numbers of senescent cells, both as a result of their toxicity and because they force cancerous cells into senescence. It is quite likely that this is the primary mechanism by which successful cancer treatments nonetheless shorten later lifespan. This could be considered a true form of accelerated aging, as the accumulation of senescent cells is one of the root causes of aging. These cells secrete signals that meaningfully disrupt tissue structure and function even when present in relatively small numbers. The research noted here doesn't make the direct connection to cellular senescence, but the cell properties examined are strongly related to levels of senescence.
Treatments for breast cancer increase patients' risks for long-term and late toxicities, including persistent fatigue, pain, and cognitive dysfunction. Certain treatments, including radiation and some chemotherapeutic drugs, work by damaging the DNA of cancer cells, but they can also cause damage to DNA of normal cells, which can contribute to accelerated biological aging.
To examine whether indicators of biological aging are related to cognitive function in breast cancer survivors, researchers evaluated a group of 94 women who had been treated for breast cancer three to six years earlier. The indicators of biological aging included elevated levels of DNA damage, reduced telomerase enzymatic activity, and shorter telomere length in certain blood cells. (Telomerase is an enzyme that is important for maintaining the length of telomeres, repeat sequences of DNA at the ends of chromosomes that help maintain the health of cells and serve as a marker of cell age.)
The team found that women who had previously been treated for breast cancer who had both higher DNA damage and lower telomerase activity had lower executive function scores. In addition, lower telomerase activity was associated with worse attention and motor speed. Telomere length was not related to any of the neurocognitive domains.
Dysfunctional Autophagy in an Alzheimer's Disease Model Unexpectedly Results in Lower Levels of Amyloid-β
Cell biology is complicated, to say the least, and so the unexpected keeps occurring. Autophagy is a collection of cell maintenance mechanisms responsible for clearing out broken structures and unwanted proteins within cells. There is plenty of evidence for its role in policing aggregates such as the amyloid-β associated with Alzheimer's disease. It is suspected that the faltering of autophagy that occurs with age is one the reasons why neurodegenerative conditions like Alzheimer's disease are a feature of late life only.
Here, researchers undertake a routine study of dysfunctional autophagy in Alzheimer's disease. They break the normal operation of autophagy via the use of mice with a mutant ubiquitin gene, and cross those mice with an Alzheimer's model lineage to obtain mice that exhibit both amyloid-β and broken autophagy. The expected result was a much more rapid accumulation of amyloid-β, as autophagic processes would fail to clear unwanted protein aggregates, but in fact exactly the opposite occurred.
Sadly, the animal models of Alzheimer's disease are highly artificial constructs, as humans are near the only species in which this condition occurs. So it is hard to say whether this has any relevance to Alzheimer's disease in humans, or whether it is a peculiar artifact of the model. This has long been a major challenge in this field of research, the sizable gap between the animal models and the real thing, much larger than is the case for other conditions. It means that any new and promising result in animal studies should be only cautiously applauded, as all too many fail to go any further.
Deposition of extracellular amyloid plaques is one of the main pathological features of Alzheimer's disease (AD), the most common cause of dementia. These plaques are composed primarily of aggregated amyloid β-peptide (Aβ), which is generated through proteolytic processing of the amyloid precursor protein (APP) by β-secretases and γ-secretases. According to the "amyloid hypothesis", accumulation of Aβ in brain is the primary influence driving AD pathogenesis. Therefore, lowering Aβ is a major therapeutic goal in AD. This might be achieved by controlling the production, aggregation, or clearance of Aβ.
The ubiquitin-proteasome system (UPS) is a highly regulated mechanism for protein breakdown in cells. It has been put forward that impaired UPS-mediated proteolysis contributes to AD pathogenesis, but the significance of the UPS in Aβ metabolism remains largely unclear. To study the effects of a chronically impaired UPS on Aβ pathology in vivo, we crossed APPPS1 mice with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based UPS inhibitor. APPPS1 mice express a chimeric mouse/human mutant APP and a mutant human presenilin 1, mutations that both represent early-onset AD, in central nervous system neurons and develop β-amyloid deposits in brain. Unexpectedly, the APPPS1xUBB+1 crossbred mice showed a decrease in plaques during aging. Also, levels of soluble Aβ42 were reduced in brain, suggesting that lower levels of Aβ42 might contribute to the decreased plaque load.
To investigate the effects of UBB+1 expression on APP processing, we carried out secretase activity measurements on brain tissue samples from different mouse lines. In APPPS1 mice, a partial decrease in γ-secretase activity was found compared to wild-type mice, in agreement with disruption of normal γ-secretase function. Interestingly, in APPPS1xUBB+1 triple transgenic mice, γ-secretase activity was partially restored, specifically at 6 months of age. Onset of amyloid plaque pathology in the APPPS1 mouse model occurs at approximately the same age. How UBB+1 exerts this stimulating effect on γ-secretase is not clear, but a potential mechanism may involve regulation of presenilin expression.
The Purpose of Longevity
Many people find there to be little distance between the questions "why live longer?" and "why live at all?" It makes it hard to have conversations about the great good that might be done through the development of rejuvenation therapies without tipping over the edge into nihilistic considerations of the meaning of life. Since life has only the meaning we grant it, these tend to be circular, pointless conversations. If you wish to live, then live.
I would say that the purpose of longevity, insofar as it has one, is to make the continuation of a life worth living a choice for those who presently have no choice, tyrannized by the their own cellular biochemistry. Rejuvenation biotechnologies, like all technologies, involve expanding the human condition by adding new choices where no such choice previously existing. Indeed, the very act of choosing itself is predicated on being alive and sound to make the choice and experience the results.
"The Purposes of Longer Lives" is the theme under which the Annual Scientific Meeting of the Gerontological Society of America (GSA) will convene in November 2018. Longevity and life span have been a core focus for GSA ever since the very first issue of the Journal of Gerontology in 1946 came bannered with the slogan, "To add life to years, not just years to life." Explicit here was the idea, dating deep into recorded history, that pro-longevity efforts should seek "not merely an increase in time per se but an extension of the healthy and productive period of life."
Today, academic units concerned with gerontology have been adding the term longevity to their titles - a center for longevity, a longevity institute. This provides organizations with a measureable outcome in a way that aging by itself cannot. At the same time, credit for gains in life expectancy is due to mortality reductions at all stages of the life course.
Longevity's purpose is a teleological question about goals and ends, about the value of extended survival. Ironically, evolutionary theory about aging tells us that longer lives for organisms are pointless beyond the stage of reproduction and perhaps the rearing of offspring. If we are to find meaning in outliving this biological design, it will need to come from human and cultural aspirations for more time alive. And more time can be valuable in at least three ways: as a personal good available for any sort of individual pursuit; as a public good that benefits the larger group; and as a resource for the scientific and scholarly study of life span - research on aging thrives on more aging.
RNA Fragments and Ribosomal Failure as a Consequence of Oxidative Stress
Researchers here describe a novel form of cell damage that results from oxidative stress, one that has not yet been investigated in any meaningful way. Oxidative stress is the name given to raised levels of oxidative molecules (free radicals, reactive oxygen species, and others) and the damage that they cause inside cells, in the form of chemical reactions that disable protein machinery. That damage is constantly occurring and constantly repaired, even in young cells, but in old cells the damage outpaces the repair mechanisms. Oxidative damage was at one time thought to be a fairly straightforward cause of aging, but that is no longer the case. It seems fairly clear nowadays that raised levels of oxidative stress in old tissues are a downstream consequence of a broad mix of other issues.
As we age, neurons in our brains can become damaged by free radicals. Researchers have discovered that this type of damage, known as oxidative stress, produces an unusual pileup of short snippets of RNA in some neurons. This RNA buildup, which the researchers believe may be a marker of neurodegenerative diseases, can reduce protein production. The researchers observed this phenomenon in both mouse and human brains, especially in a part of the brain called the striatum - a site involved in diseases such as Parkinson's and Huntington's.
For this study, the researchers used a technique that allows them to isolate and sequence messenger RNA from specific types of cells. This involves tagging ribosomes from a specific type of cells with green fluorescent protein, so that when a tissue sample is analyzed, researchers can use the fluorescent tag to isolate and sequence RNA from only those cells. This allows them to determine which proteins are being produced by different types of cells.
n separate groups of mice, the researchers tagged ribosomes from either D1 or D2 spiny projection neurons, which make up 95 percent of the neurons found in the striatum. They labeled these cells in younger mice (6 weeks old) and 2-year-old mice, which are roughly equivalent to humans in their 70s or 80s. The researchers had planned to look for gene expression differences between those two cell types, and to explore how they were affected by age. To the researchers' surprise, a mysterious result emerged - in D1 neurons from aged mice (but not neurons from young mice or D2 neurons from aged mice), they found hundreds of genes that expressed only a short fragment of the original mRNA sequence. These snippets, known as 3' untranslated regions (UTRs), were stuck to ribosomes, preventing the ribosomes from assembling normal proteins.
The 3' UTR snippets appeared to originate from about 400 genes with a wide variety of functions. Meanwhile, many other genes were totally unaffected. The researches found that the activation of oxidative stress response pathways was higher in D1 neurons compared to D2 neurons, suggesting that they are indeed undergoing more oxidative damage. The researchers propose a model for the production of isolated 3' UTRs involving an enzyme called ABCE1, which normally separates ribosomes from mRNA after translation is finished. This enzyme contains iron-sulfur clusters that can be damaged by free radicals, making it less effective at removing ribosomes, which then get stuck on the mRNA. This leads to cleavage of the RNA by a mechanism that operates upstream of stalled ribosomes.