Fight Aging! Newsletter, July 2nd 2018

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

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  • Some Benefits of Intermittent Fasting are Mediated by the Gut Microbiome
  • Suggesting that Lower Levels of NAD+ Increase Cellular Senescence in the Retina
  • Calico Extends a Sizable Partnership, Remains Otherwise Uncommunicative
  • The Mitochondrial Transition Pore in Age-Related Mitochondrial Dysfunction
  • Glial Cells in Aging and Neurodegeneration, in Flies and Mammals
  • Improving the Understanding of Chronic Inflammation in Atherosclerosis
  • An Interview with Vadim Gladyshev on Research into the Causes of Aging
  • Humans Before Humanity; Individuals Before Abstract Groupings
  • Structured Exercise is Good for the Elderly
  • Naked Mole Rats Repair DNA Damage More Efficiently than Mice
  • Late Life IGF-1 Inhibition Modestly Extends Life in Female Mice Only
  • A First Pass at Artificial Cell Structures Capable of Influencing the Immune System
  • Unity Biotechnology Starts First Human Trial of a Senolytic Therapy
  • Interfering in an Amplification Loop for Oxidative Stress in Aging Mice
  • Back to Arguing for a Mortality Rate Plateau in Extremely Old Humans

Some Benefits of Intermittent Fasting are Mediated by the Gut Microbiome

There is a growing interest in the role of microbial populations of the gut in aging and health, with evidence from recent years suggesting that their level of influence might approach that of exercise. Some fraction of the benefits to health and longevity that occur due to the practice of either calorie restriction or intermittent fasting are thought to be mediated by resulting changes in gut microbe populations. This seems a safe assumption, given the evidence to hand, but the still open question is just how large or small that fraction might be. The consensus view remains that benefits largely result from increased cellular housekeeping, and the fact that calorie restriction fails to work in animals with disabled autophagy is telling.

Complicating the matter, however, calorie restriction and intermittent fasting are not just two ways of achieving exactly the same result. They produce significantly different patterns of gene expression in animal studies. Intermittent fasting without reducing calorie intake still produces health and longevity benefits in rodents. Calorie restriction lasting for less than three days in humans fails to produce the significant benefits to immune cell populations that fasting for four or longer days achieves. One could argue that the point is time spent in a state of hunger, but that seems overly simplistic given what is known. A mammalian body and its microbial fellow travelers are collectively a complicated system, and that system has correspondingly complicated responses to environmental circumstances.

In the open access paper here, researchers focus on one specific set of interactions between gut microbes and the immune system. Age-related (and other) changes to the microbiome can contribute to chronic inflammation and autoimmunity - here, the autoimmune condition in question is multiple sclerosis, in which immune cells attack the myelin sheathing of nerves, with catastrophic consequences. Intermittent fasting can help in this situation by reducing the influence of problematic microbial populations.

As is the case in all such investigations, the highly varied and dynamic nature of the gut microbiome makes it hard to settle on definitive results that are true for everyone at all times. Even for a given individual, what turns out to be a beneficial influence one year might be more or less beneficial the next year, because the state of the gut mitobiome shifts over time. Of all the presently available ways to manipulate gut bacteria, forms of calorie restriction appear the most reliable, but the degree to which they work in this matter is greatly obscured by the other reliable benefits they achieve in the operation of cellular metabolism.

Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota

Multiple sclerosis (MS) is more common in western countries. Dietary habits have been considered as a potential factor contributing to MS epidemiology. Different diets and dietary supplements have been implicated in MS risk, but the field is lacking robust scientific data to support this risk. Indeed, many studies highlight the importance of the complex interplay between nutrition, metabolic state, and immune-inflammatory responses in MS. Obesity during childhood/young adulthood is a risk factor for MS development as shown in several recent studies. This might be related to a low-grade chronic inflammatory state in obesity that could promote autoimmunity through altered adipokine production. An additional link between nutrition and immune-inflammatory responses is the gut microbiome. Diet is a critical determinant of the gut microbial composition. Gut commensal bacteria and their metabolites have the potential to exert both pro- and anti-inflammatory responses by regulating T cell differentiation and immune responses in the gut. Ultimately, this can have systemic effects and either drive or protect from autoimmune diseases.

Recently it has been reported that the gut microbiome in relapsing-remitting multiple sclerosis (RRMS) patients is altered compared with healthy controls. Further, calorie restriction (CR) has potent anti-inflammatory effects. Studies, including our own, demonstrated that chronic CR significantly inhibited progression of the MS model, experimental autoimmune encephalomyelitis (EAE). However, chronic CR is not likely to be feasible for most people. Intermittent fasting (IF) induces many of the same changes observed by chronic CR and would possibly be more acceptable. We therefore undertook studies of IF in the EAE model and in MS patients experiencing a relapse and showed that IF ameliorated EAE through effects at least in part mediated by changes in the gut flora.

IF induced protective changes in gut microbiome metabolic pathways and lamina propria lymphocytes as demonstrated by the fact that gut microbiome transplantation from mice on IF ameliorated EAE in recipient mice after immunization. To translate our findings in patients, we performed a small pilot randomized controlled trial. IF in MS patients having a relapse was a safe and feasible intervention associated with short-term metabolic and gut microbiome changes that recapitulated what was observed in the animal model.

IF had a striking effect on gut microbiota composition with enrichment of the Bacteroidaceae, Lactobacillaceae, and Prevotellaceae families. In EAE, alteration of the gut microbiota or their metabolites can modulate inflammation and demyelination. Of particular interest was the IF-induced enrichment in Lactobacilli, which are commonly used in probiotics because of their positive effects, including reduction of inflammatory immune responses. In the present studies, Lactobacillus species that were over-represented in the setting of IF included L. johnsonii and L. reuteri, which are well known to have immunomodulatory properties. In addition, enrichment in Prevotella family members with IF may be beneficial because of its enhancement of production of protective short chain fatty acids (SCFAs), such as butyrate. This is important because SCFAs are bacterial metabolites derived from indigestible carbohydrates that have been reported to inhibit EAE by expanding gut regulatory T cells.

Suggesting that Lower Levels of NAD+ Increase Cellular Senescence in the Retina

Present investigations and attempts to influence nicotinamide adenine dinucleotide (NAD+) metabolism in aging might be viewed as the direct descendant of the heavily hyped sirtuin research of a nearly decade ago. We can check the boxes for (a) mechanisms linked to mitochondrial activity, (b) supplements claimed to adjust age-related changes in those mechanisms, and (c) many of the same people in the scientific community being involved. At the end of the day this may well arrive at the same destination as that sirtuin development, which is to say nothing of any practical use to improve human longevity, but at least the outcome of an incrementally greater understanding of this narrow section of mammalian cellular metabolism.

The data for benefits to result from some of the presently available supplements that might increase NAD+ levels is admittedly considerably better than was the case for tinkering with sirtuins, but that is nonetheless a low bar to pass. Even so, some of these approaches clearly produce the same old story of unreliably, tiny effects that tend to vanish given more care and more rigorous studies. The best outcome we could hope for in the near future is a modestly useful exercise mimetic that can help the unfit to evade some fraction of the consequences of their lack of fitness. Rigorous data has yet to arrive, however, and it could all still come to nothing much yet. That best outcome is still not rejuvenation in any meaningful sense. It is tinkering with the damaged machinery, hoping to get a few extra percentage points of operational capacity out of it, without actually trying to fix the breakages.

Does loss of NAD+ and related decline in mitochondrial function affect the processes that cause cells to become senescent, and thereafter linger and cause harm to surrounding tissues? Since mitochondria are central to most aspects of cellular health, by virtue of providing the chemical energy stores needed for the cell to run at all, and are also central to the processes of programmed cell death that determine whether senescent cells self-destruct or linger, this seems plausible. The details matter, however: what is the size of the effect, in comparison to, say, the decline of the immune system, or other factors in age-related mitochondrial dysfunction, in determining how many senescent cells are present in a tissue? How does it vary between tissues? Further, the methodology used here to reduce NAD+ levels may or may not be a good substitute for what takes place in aging; as a general rule, few such models are, and it is always a question of whether or not the differences happen to be large enough or relevant enough to be a problem for the present area of interest.

Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence

The retinal pigment epithelium (RPE) performs numerous functions essential to normal retinal health and function. RPE is implicated directly and prominently in the pathogenesis of most degenerative diseases of the retina, including age-related macular degeneration (AMD), the leading cause of blindness among persons aged 60 and above worldwide. AMD is a complex multifactorial disease and, as its name implies, age is a primary risk factor for its development.

Interestingly however, most available experimental models and related studies have focused more heavily on identifying, understanding, and limiting secondary consequences of aging and related RPE dysfunction (e.g., increased oxidative stress, inflammation, altered cholesterol metabolism) as opposed to targeting directly factors, such as energy deprivation, that precipitate accelerated aging at a cellular level. The consequence of the latter is an imbalance in homeostatic processes and subsequent damage, as shown in many specific cell types. This is the premise of a number of recent studies including the present investigation in which we focused on nicotinamide adenine dinucleotide (NAD+) and factors governing its bioavailability in relation to the overall impact on RPE viability.

NAD+, a central metabolic cofactor, plays a critical role in regulating cellular metabolism and energy homeostasis. The ratio of NAD+ to NADH (oxidized to reduced NAD+) regulates the activity of various enzymes essential to metabolic pathways including glycolysis, the Kreb's cycle, and fatty acid oxidation. There is a wealth of clinical and experimental data stemming from studies of other primary diseases of aging demonstrating clearly a generalized decline in the availability of NAD+ in association with increased age and the related reduction in the activity of a number of downstream metabolic pathways that contribute to the development and progression of degenerative processes.

Neuronal cells and tissues appear to be especially sensitive in this regard. Importantly, the aforementioned studies additionally suggest that age-related degenerative processes might be prevented or at the least, the consequences thereof lessened in severity by therapies that boost NAD+. In the present investigation we focused on evaluating the impact of NAD+ and factors that regulate its availability on RPE viability both in vivo and in vitro. Cellular senescence is a common consequence of aging hence, the decline in NAD+ in RPE and the associated upregulated expression of markers of senescence that we observed was not totally surprising. Though there has been some debate over whether dysfunction occurs first in the RPE or in the overlying photoreceptors, the contribution of senescence-associated RPE damage to age-related RPE dysfunction is undeniable.

Here, using adult C57BL/6J mice across a broad range of ages (2-18 months), we first confirmed that NAD+ levels decline significantly in association with increased age as has been reported to occur in other retinal and non-retinal cell types. Our related evaluation of enzymes that drive key steps in NAD+ biosynthesis revealed NAMPT as the enzyme principally responsible for maintaining adequate NAD+ levels in RPE. This is congruent with recent work by others demonstrating that NAMPT-mediated NAD+ biosynthesis is essential for proper visual function. We used the compound to optimize a cell culture model system that allowed us to simulate and study the impact of decreased NAMPT expression and related NAD+ availability on RPE cell viability relevant to aging. Our studies in the human RPE cell line ARPE-19 demonstrated an increase in RPE cell senescence in conjunction with reduced NAMPT and NAD+ availability as indicated by analyses of the expression of senescence markers.

Our present data demonstrating an age-dependent decline in NAMPT expression and in turn, NAD+ generation in RPE which ultimately promotes RPE senescence supports strongly the rationale for enhancing NAMPT expression and associated NAD+ generation therapeutically. Indeed, such therapies may represent a viable strategy for preventing and treating RPE and consequent photoreceptor damage in aging/AMD and broadly, in other degenerative retinal diseases in which RPE is prominently affected.

Calico Extends a Sizable Partnership, Remains Otherwise Uncommunicative

Those of us who do not work at the California Life Company, Calico, have very little idea as to what it is the staff there are up to, at least when it comes to the details. The organization is very heavily funded by the overspill of resources from Alphabet, employs a great many scientists, and - so far as the world peering in from the outside can determine - is engaged in fundamental aging research with the goal of producing pharmaceutical treatments to intervene in the aging process at the end of the day. The little research they have made public is very distant from SENS and the idea of repairing damage, and looks more likely to lead to the same old story of manipulating the operation of metabolism in order to modestly slow the progression of aging.

But it is very hard to say. Calico could be undertaking an energetic senolytics program, or otherwise be working on something quite interesting to the SENS rejuvenation research community. We have no idea. The dominant character of the organization is secrecy: those working there and those in charge say nothing about what they are doing. It makes it hard to criticize the principals on anything other than that count, which might be the intent. That said, I think most of us have by now written off Calico as the second coming of the Ellison Medical Foundation, which is to say a sizable investment in extending the day to day work of the National Institute on Aging, carrying out projects focused on the details of the progression of aging that, while advancing the state of knowledge, are unlikely to produce meaningful therapies at the end of the day.

Even that knowledge, covering the molecular biology of the progression of aging in humans without access to rejuvenation therapies, will be obsolete a few decades from now. It will not actually have helped all that much to bring about the era of rejuvenation therapies. Those therapies will emerge from the SENS-focused and other similarly oriented research communities, those building ways to repair the well-described molecular damage that distinguishes old tissues from young tissues. Creating proficient means of damage repair does not require any great knowledge of how exactly that damage progresses to disease and death: just fix it and observe the outcomes. Further, damage repair will always outperform efforts to tinker with the damaged state without repairing it - and it doesn't much matter whether we are talking about an electronic device, an automobile, or a mammal. The principle is the same. Calico seems like a missed opportunity at this point, some years down the line from its creation.

A monster discovery deal between AbbVie and Google's Calico gets a new lease on the lab, with 1B more to back aging research

Nearly 4 years after AbbVie and Google's fledgling Calico stepped up to the altar of drug science and committed themselves to a 1.5 billion partnership on developing a pipeline of anti-aging drugs, they've decided to renew their vows. And this time they're backing it up with a joint 1 billion pledge - 500 million each - to keep the alliance going for some years to come, with an eye to slowly stepping up the relationship in a move toward the clinic. In a rare public display of affection, the two companies are touting the advance of more than two dozen late discovery projects, with a special focus on cellular stress that they believe has some profound long term implications for human health. Another piece of info: The famously quiet Calico has built a big team of 150-plus around an HQ base in South San Francisco, with plans to add more.

But that's about it. If they are working on a revolution in drug development aimed at putting more life into lengthy spans of living, don't expect any claims along the way about curing cancer, or diabetes, or arthritis in mice. Press execs on what they've been working on, though, and you get pointed to a long lineup of papers Calico has published on their work, but no specifics on the most promising targets in their chosen field. How about the budget? Did they spend the 1.5 billion? Nothing. "We're not going to be specific about molecular targets. It hasn't been in our nature to hype about what we have. What I can tell you is that we are very pleased with the progress of the collaboration. We have a number of potential viable clinical programs. Our interest in aging goes to the basic roots of aging."

The Mitochondrial Transition Pore in Age-Related Mitochondrial Dysfunction

Every cell contains a herd of bacteria-like mitochondria. These are the power plants of the cells, responsible for packaging chemical energy store molecules. They replicate by division, but also fuse together and exchange component parts. For reasons that are far from fully understood, the mitochondria in old tissues are much changed and degraded in comparison to their counterparts in youthful tissue. Their shapes are different, the balance of fusion and fission altered, they generate too little in the way of energy store molecules and too much in the way of oxidative molecules. Some of this is a matter of damage to mitochondrial DNA, which produces its own additional serious set of downstream issues, but much of it seems more akin to a reaction to damage and altered signaling in cells and the surrounding tissue, rather than any inherent malfunction in the mitochondria themselves.

To the degree that this global mitochondrial malaise is a consequence of the accumulated damage and resultant changing character of signaling in aging, then it should end if the root causes of aging are addressed. When the chronic inflammation, altered cell signaling, and issues elsewhere in cell structures are reversed, then we should expect mitochondrial function to improve in turn. This strategy of identifying and fixing root causes is still a minority approach in research and development, however. Most work on mitochondrial aging is focused instead on finding ways to override some of the signals that produce mitochondrial loss of function, to eke out greater capacity for a longer period of time. The history of such approaches doesn't provide much confidence in the ability of the research community to produce large gains via such an approach, however. The best plausible near future therapies are forms of exercise mimetic, perhaps, and those people who exercise a great deal don't live more than a small number of years longer than the rest of us.

Mitochondria and aging: A role for the mitochondrial transition pore?

Mitochondria are central organelles in the cell. They are present in all cells of humans and animals (except red blood cells). They generate cellular energy, produce reactive oxygen species (ROS) that regulate physiological processes, and are involved in the control of cell death. Therefore, it is not surprising that mitochondria could be involved in the normal mammalian aging process. One of the unique characteristics of mitochondria is that they possess their own genetic material in the form of a close circular DNA molecule. According to this latter theory, aging of cells would be due to the constant delivery of ROS inside mitochondria throughout life, damaging mitochondrial DNA which is vulnerable as it is not protected by protein histones or repairing enzymes such as nuclear DNA. The damaged mitochondrial DNA leads to deficiency of key electron transport enzymes and subsequent ROS generation, thus causing a vicious cycle of ROS resulting in a decrease in energy production.

Although a large amount of data support the role of mitochondrial ROS production in aging, other features of mitochondrial physiology and dysfunction, including the mitochondrial permeability transition, have been more recently implicated in the mechanisms of aging. The mitochondrial permeability transition corresponds to the sudden increase in the permeability of the inner mitochondrial membrane to molecules of molecular mass up to 1,500 Da. The opening is due to a nonspecific pore called the mitochondrial permeability transition pore (mPTP) occurring when mitochondria become overloaded with calcium. The sensitivity of the mPTP to calcium is enhanced under oxidative stress conditions, adenine nucleotide depletion, high phosphate concentrations, or membrane depolarization. mPTP opening induces swelling of the organelle matrix, collapse of membrane potential, and uncoupling of oxidative phosphorylation. This phenomenon plays a critical role in different types of cell death. Although the conditions leading to permeability transition are well known, the exact composition of the pore remains unknown.

Currently, a common agreement considers that cyclophilin D (CypD), a soluble protein located within the mitochondrial matrix, is the main partner of the mPTP and that mPTP formation is greatly sensitized by CypD which lowers the calcium threshold required to trigger mPTP opening. The crucial role of CypD has been shown by deletion of the gene in mice, allowing mitochondria to sustain high calcium concentrations and thus conferring major desensitization of mPTP. Two opening states of the pore have been distinguished, a permanent or long-lasting state which is associated with cell death, and a transient opening state having a physiological role by providing a pathway to release ROS and calcium from mitochondria which is also regulated by CypD. The mPTP is now considered to be central in numerous conditions such as heart, brain, or liver ischemia-reperfusion, drug-induced liver injury, age-related neurodegenerative diseases, and accumulating data imply the mPTP in organ dysfunction occurring during aging. Conversely, caloric restriction, which is a proven strategy to delay aging and age-related disease, is associated with the inhibition of mPTP opening.

Recently, a large number of studies demonstrated that the mPTP, which is not definitely characterized at the molecular level, is more sensitive to opening in aged animals and in aging-associated diseases and that its inhibition can enhance lifespan. This appears logical as the cellular modifications occurring during aging, that is, impaired calcium homeostasis, increased oxidative stress, oxidative modifications of proteins, enhancement of CypD level, and apoptosis, are factors contributing to and modulated by mPTP opening. However, doubts persist about the involvement of mPTP in the progression of aging and definitive experimental proofs of mPTP involvement have to be provided to demonstrate whether it is a cause or a consequence of aging. A better knowledge of the structural composition and of the regulation of the pore will probably help to elucidate the role of mPTP in longevity and healthspan.

Glial Cells in Aging and Neurodegeneration, in Flies and Mammals

Various forms of glial cell exist in the brain, supporting and protecting neurons. Over the years, researchers have discovered that glial cells are deeply involved in many of the important functions of neurons, such as the establishment and maintenance of synaptic connections. Some forms of glial cell, such as microglia, are a part of the innate immune system. They differ in many aspects from similar types of immune cell elsewhere in the body, macrophages, but have much the same set of responsibilities: clean up debris; consume pathogens; destroy errant cells; assist in regeneration from injury. In the aging brain, immune dysfunction sets in similarly to the rest of the body. Immune cells become overly activated, inflammatory signaling grows, but at the same time the immune system becomes less capable of carrying out its core tasks.

Of late, the research community has devoted increasing attention to the balance of states in microglia and macrophage populations. These cells have a number of overlapping states, or polarizations, a way of characterizing their behavior. The M1 state is less helpful in regeneration, and more inflammatory and aggressive in pursuit of pathogens. The M2 state, on the other hand, suppresses inflammation and helps to generate a supportive environment for regeneration. A wide range of age-related conditions are characterized by the presence of too many M2 and too few M1 microglia or macrophages, likely one of the many complex detrimental reactions to accumulations of underlying cell and tissue damage. Adjusting this balance many prove to be helpful, even in the absence of efforts to address low-level damage, but reliable methods of achieving that goal have yet to emerge.

In this open access paper, the authors review the present state of research into glial cells and aging in flies, and the relevance of these studies to the understanding of mammalian aging. They focus on parts of the bigger picture in which enough is known to pick out relationships, but not yet enough to understand how the same mechanism can apparently contribute to both neurodegeneration and defense against neurodegeneration. Cell metabolism is complex, the immune system is complex, and the brain is particularly complex. These are good reasons not to try too hard to intervene downstream from the comparatively simple root causes of aging; if less complicated opportunities arise, then by all means, but in most cases trying to manipulate the damaged state of metabolism is an expensive path to poor results.

Role of Glial Immunity in Lifespan Determination: A Drosophila Perspective

The chronic inflammatory status that accompanies human aging, also known as inflammaging, is considered a significant risk factor for many chronic pathologies including cancer, cardiovascular and neurodegenerative disorders. In the context of aging, increased levels of pro-inflammatory cytokines such as TNF-alpha and Interleukine (IL)-6 are found upregulated in brain tissue. With age, mammalian microglia, which are the brain immune cells exhibit primed profile characterized by increased activation and enhanced secretion of pro-inflammatory cytokines. Decline in microglial function, migration, and chemotaxis are also observed with age. For instance, microglia's engulfment capacity of amyloid-beta (Aβ) or alpha-synuclein (α-Syn) oligomers, whose accumulation is characteristic for Alzheimer's and Parkinson's disease, respectively, are compromised in aged animals. Moreover, activated microglia and neuroinflammatory profiles are observed in most neurodegenerative disorders.

Drosophila, the common fruit fly, is an excellent versatile model organism to investigate the interplay between innate immune function and brain physiology among the effects of this interaction to host lifespan. There is a high degree of evolutionary conservation of the molecular mechanisms of innate immunity between flies and mammals. Similar to mammalian models, both chronic innate immune activation as well as decline in phagocytic activity of glia are observed in the aging Drosophila brain. It is thus apparent that glial immunity is linked to both, healthy aging and age-dependent neurodegeneration.

In the mammalian brain, under normal physiological conditions, microglia provide the first line of defense against brain injury and infection. These cells are able to sense pathogens via pathogen recognition receptors, activate innate immune signaling pathways, phagocytose microorganisms, and clear cellular debris. Microglia also have the capacity to secrete neurotrophic factors and anti-inflammatory molecules, therefore, playing a protective role in these contexts. On the other hand, the neurodegenerative process itself can trigger inflammation, leading to detrimental effects on the brain. It is, therefore, important to understand the mechanisms by which, changes in the same signaling pathway (e.g., NF-kB) lead to two distinct phenotypes, namely healthy aging associated with neuroprotection and neurodegeneration.

It is becoming increasingly evident that glial cells play an important role in neuroprotection and in organismal physiology throughout lifespan. In the recent years, studies in the model organism Drosophila have revealed numerous aspects of glial contribution toward both, healthy aging, and the development and progression of age-related pathologies of the nervous system. Dysregulation of glial innate immune reactions such as improper NF-κB signaling or impaired Draper-based phagocytosis results in early onset neurodegeneration and lifespan shortening. Thus, both branches of the innate immune response seem to contribute in host neuroprotection and longevity. Additional work is needed to investigate whether these two pieces of the innate immune response possess synergistic properties and identify possible cellular factors that regulate both the inflammatory and phagocytic pathways in glial cells.

Improving the Understanding of Chronic Inflammation in Atherosclerosis

Atherosclerosis is an inflammatory condition. Oxidized lipids lead to the formation of fatty plaques that narrow and weaken blood vessels, the growth of those plaques driven by the activities of macrophages that try and fail to repair the damage. They become overwhelmed and die: plaques are a mix of fat and the cellular debris from dead macrophages. Prior to their destruction, macrophages generate inflammatory signaling as atherosclerosis worsens, but how is it that other sources of age-related chronic inflammation can accelerate the progression of atherosclerosis? Researchers here explore some of the less well-understood parts of the feedback loop between inflammation and mechanisms of atherosclerosis, in search of answers.

Investigators have identified a new cellular pathway that may help explain how arterial inflammation develops into atherosclerosis - deposits of cholesterol, fats, and other substances that create plaque, clog arteries, and promote heart attacks and stroke. "We have known for decades that atherosclerosis is a disease of chronic inflammation that ultimately results in the scarring of arteries and tissue damage. But the ongoing stimulus for this inflammation has been unclear."

A new study sheds light on this mystery by using a bacterial infection to reveal a cascade of cellular events that can lead to inflammation and atherosclerosis. Investigators focused on interleukin-1 beta, a type of protein that is assembled and released by immune system cells in response to infection and injury, including tissue damage caused by atherosclerosis. While interleukin-1 beta helps rally the immune system against these threats, it also can cause chronic inflammation. The study team wanted to understand how the interleukin-1 beta pathway might promote atherosclerosis.

To make its way out of the immune system cell, interleukin-1 beta can also use the same chemical channels that are used by cholesterol to exit the cell. The result is a "traffic rush" on those channels that blocks the exit of artery-damaging cholesterol and causes it to accumulate in the cell. Once it is released by the cell into the body, interleukin-1 beta suppresses a chemical receptor that enables niacin to be used in the body. This action is harmful because niacin works by removing cholesterol from cells in the artery walls. When niacin is blocked, cholesterol can accumulate in the walls. The suppression of the niacin receptor has another negative effect: It reduces the number of chemical channels that cholesterol uses to exit the immune system cell, causing more cholesterol to be trapped inside. That is because the niacin receptor, besides enabling niacin, also increases these channels as part of its normal function.

These discoveries are especially significant because drugs that inhibit interleukin-1 beta have shown promise in combating atherosclerosis and heart disease. A major clinical trial, led by another research institution and published last year, reported that administering one such drug to patients who had a prior heart attack reduced inflammation and lowered the risk of another cardiovascular event. The study raises the possibility that by using drugs to block the initial production of interleukin-1 beta, rather than just neutralizing it, a stronger positive effect could be obtained for these patients.

An Interview with Vadim Gladyshev on Research into the Causes of Aging

The Life Extension Advocacy Foundation volunteers recently interviewed researcher Vadim Gladyshev. He has an interesting viewpoint on aging; he is one of the faction in the scientific community who think that near future significant progress in treating aging is unlikely, as greater understanding is required. This is more or less the polar opposite of the SENS rejuvenation research viewpoint, which states that the present understanding of the root causes of aging is sufficient for progress, and implementation is lagging far behind the state of the science. Gladyshev's laboratory is focused on the genetics of aging and redox biology - the modern end of the evolving view of how oxidative damage is involved in aging.

The early views of aging as being driven by an accumulation of oxidative damage to important molecules have been put aside as too simplistic. Numerous examples of life extension in lower animals have involved modest increases in the production of oxidative molecules: oxidation isn't just a form of damage, it is also a signal in a very dynamic, self-repairing system, one that can have positive outcomes. Oxidative molecules are required for the benefits of exercise to manifest themselves, for example, and those benefits can be blunted by overuse of antioxidants. So while it is clearly the case that older individuals have far greater levels of oxidation in their cells and tissues, that is probably secondary to issues such as mitochondrial and immune system dysfunction.

Why do you think we age?

We age because the process of living is associated with deleterious consequences (in the form of molecular damage, mutations, epigenetic drift, imbalance, dysfunction, etc.), which accumulate over time. We call these deleterious changes the deleteriome, as they are much broader than molecular damage. So, we age because of the increasing deleteriome.

Some scientists suggest that aging is a disease or, more specifically, a co-morbid syndrome; would you agree with this?

I think aging is neither a disease nor not a disease. On one hand, aging is a process, whereas disease is a condition. So, the question may need to be reformulated to whether being older is equivalent to having a disease. On the other hand, conceptually, both aging and disease are associated with deleterious changes, with pathology. Therefore, I think aging includes a combination of chronic diseases together with their preclinical development and other age-related, deleterious changes.

According to our current understanding, aging is the result of the accumulation of different types of damage and errors in the body. Which of these issues do you think will be the hardest to address?

Aging is not only the result of the accumulation of damage and errors but also other deleterious changes. This is why I think the term 'deleteriome' better reflects what happens during aging. In live organisms, every biological process produces deleterious changes. These changes are so diverse and numerous that it would be impossible to fix them all or even sense most of them. Instead, it may be best to alter an organism so that it accumulates fewer deleterious changes (i.e. its deleteriome grows slower) or dilute damage by cell replacement and cell division. I think focusing on a particular damage form is akin to focusing on a particular age-related disease. This approach has some merit, but it would not stop, reverse, or even significantly affect aging, as there could be no main or major damage form. Damage and other deleterious changes act together and need to be dealt with together if we are to target the aging process itself.

What piece of the aging puzzle are you and your lab tackling right now?

We work both on mechanisms of aging and mechanisms of longevity. To begin to target aging, first we need to understand what aging is, which, in turn, should lead to better approaches for lifespan extension. An important element in this research is the ability to measure the biological age of organisms. The first-generation biomarkers of aging, most notably the DNA methylation clock but also other clocks, have now been developed, and they should be useful in testing longevity interventions, rejuvenation approaches, and other treatments and manipulations. For this purpose specifically, we have developed the mouse blood DNA methylation clock.

Different scientists have different views on how close we are to developing the first rejuvenation therapies against human aging. What do you think?

We are not close. We do not even agree on what aging is, when it begins, whether aging is a disease, or what exactly should be targeted. If we consider the analogy to the history of chemistry, we are just moving away from alchemistry and developing the first chemical principles. In aging, we do not yet have the analog of the periodic table. As a field, we often apply approaches akin to alchemists trying to make gold from other metals. I firmly believe that we cannot solve the problem before we understand it, and the longer we avoid trying to understand it, the longer we will remain aging alchemists.

Humans Before Humanity; Individuals Before Abstract Groupings

Valuing abstract measures of the welfare of a group distinctly and separately from the welfare of the individuals making up that group is a particularly pernicious conceptual invention. Its most recognizable modern incarnations are nationalism and patriotism, but it has been serving as cover for inhumanity and disregard for considerably longer than that. It also serves as a way for people to argue against treating aging as a medical condition: the group is just fine, thank you, and thus it doesn't matter that all of the individuals in that group are doomed to suffer, diminish, and die. So why do anything about it? A healthier view of the world is that only individuals and their interactions with one another matter, but making that the default mode of thought is something of a challenge in an era of strong centralized governance and wall to wall propaganda for the nation state concept as an entity more important than its citizens.

One of the innumerable romanticizations of death that we're often presented with is that, as one generation dies out, it's just passing on the responsibilities of life to the next. Someone else will take on the task of perpetuating the species, and in general, it doesn't really matter who it is. Never mind that we all die; as long as there's someone to pass the torch to, somebody who will continue to play for team humanity, that's all it matters.

Humanity is not a football club, and neither are other, smaller groups of humans. The family of my great-grandfather, intended as himself, his wife, and their children, is dead. Their genes are still around, and other families have descended from them, in some case even bearing the same family name (another abstraction), but the specific individuals making up my great-grandfather's family are gone, and so is that specific family. You might argue that they're still alive in their descendants' memories and genes or that their name is being passed down, keeping alive the family, but these are all mental gymnastics to present the fact that they're dead in a less unappealing fashion. They're dead, and whether someone still remembers anything about them, or carries a few of their genes or their name, doesn't make them any less dead.

On the subject of future generations, one often hears that their well-being depends on our actions today, and thus we should work to leave them with a better world than we had; this is a commendable intention, and, in fact, it is one of the reasons why we should develop rejuvenation - to spare future human beings the plague of age-related diseases. However, future generations are not here yet; we are, and it's rather mystifying how everyone frets about the currently nonexistent needs of people yet to come but not so much about the very real needs of people who already exist. Today, people suffer from, and die of, age-related diseases; it's a concrete problem, with tangible effects on the world at large in the present; yet many people seem to worry more about the potential problems they imagine that rejuvenation might cause to future.

So, who's more important? Individuals or humanity? It should be clear by now that we'd better think in terms of individuals. The good of humanity shouldn't be about maintaining our presence in the universe just for the sake of being here; it should be about the well-being and life quality of the individuals that make up humanity - and when they're dead, or about to die, individuals aren't generally doing very well. Being concerned about future generations is both understandable and commendable, but it should not lead us to neglect who's already here. As long as we exist, and our good is taken care of, the preservation and the good of humanity will be ensured as well; future humans are welcome to join.

Structured Exercise is Good for the Elderly

Lack of exercise is harmful to health at all ages, and we live in a sedentary era, coddled by our machineries of transport and convenience. A perhaps surprisingly large degree of the decline into frailty is caused by the lack of exercise that sets in for many adults, and particularly lack are the forms of resistance training that builds strength. Thus there are plenty of studies like the one noted here that demonstrate benefits in elderly individuals who take up a structured program of exercise: most older people do not exercise as much as they can and should, and the consequence of that is a lower quality of life and higher mortality rate.

During ageing, regular exercise may reverse age-related physical deterioration and, at the same time, frailty, a very common syndrome among the elderly and which entails a higher risk of falls, hospital admissions, dependence and even death. This syndrome is more widespread among people living in residential care homes. In order to improve the life quality of this group, researchers designed a programme of physical exercise adapted to the capabilities of each individual. Strength, balance and stamina are worked on. The programme is run progressively and the intensities are increased as the capabilities of the people, for whom the adaptations of the body are greater, increase.

The effectiveness of the programme was analysed in a sample of 112 participants from 10 centres for the elderly. They were randomly divided into two groups: the control group that continued with its usual activities and care, and the experimental group that did two 45-minute sessions of physical exercise per week designed to improve strength and balance. The time they spent walking was gradually increased until they reached at least 20 minutes a day.

After three months, the study showed a significant improvement in most of the physical variables, such as strength, walking speed, and balance in the people who were doing physical exercise. By contrast, the people in the "control" group saw a reduction in their physical capabilities. The results obtained in the SPPB (Short Physical Performance Battery) were particularly significant. These tests are used to measure the degree of frailty and may predict the risk of falls, hospital admittances, dependence or death. Doing physical exercise generated a two-point increase in the SPPB while the result for the control group fell by one point. "A difference of a single point on this scale is already regarded as significant; 3 points are a clinically highly significant difference."

Naked Mole Rats Repair DNA Damage More Efficiently than Mice

Naked mole rats live nine times longer than other, similarly sized rodents. They are also near immune to cancer. Researchers are mining the biochemistry of this species in search of mechanisms that might inform the development of ways to treat cancer or influence the processes of degenerative aging. Cancer is a consequence of mutation in nuclear DNA, and the consensus of the majority of the research community is that this random mutational damage, expanded out into large numbers of cells when it occurs in stem and progenitor cells, is a meaningful cause of aging. Thus should we expect naked mole rats to have highly effective DNA repair in comparison to short-lived rodents? It seems to be the case that they do.

Aging and cancer are accompanied by the accumulation of mutations in the genome, genomic instability and dysregulation of transcription patterns. DNA repair systems have evolved to counteract genomic instability. However, whether long-lived and cancer-resistant animal species have more efficient DNA repair is unclear. The naked mole rat (NMR), Heterocephalus glaber, is the longest-lived rodent with the maximum lifespan of 32 years, which is almost ten times longer than a house mouse. Furthermore, NMRs are resistant to cancer with spontaneous tumors being extremely rare.

NMRs evolved a variety of adaptations that may contribute to longevity and cancer resistance. Some of these adaptations may promote genome and proteome stability and increase resistance to stress. NMR proteins involved in redox processes are more resistant to denaturing agents and are able to maintain function under oxidative stress. High accuracy of translation process, increased level of expression of key chaperones and more active proteasomes help to maintain a pool of functional proteins.

Transcriptome analyses by RNA sequencing showed that several genes involved in DNA repair are up-regulated in H. glaber cells. However, transcript levels do not always unambiguously reflect the level of protein expression and activity. NMR cells were found to be more resistant than mouse cells to a variety of stressors. Cell survival under stress is a function of the repair capacity, cell cycle checkpoints, and apoptotic responses. Therefore, NMRs may have more efficient base excision repair (BER) and nucleotide excision repair (NER) systems that protect the cells from mutations coupled with heightened stress responses.

Here we performed the analysis of BER and NER systems in NMR and mouse fibroblasts in response to UVC-light exposure. We evaluated post-irradiation changes in mRNA transcription of several key reparative proteins and measured the activities of the key BER and NER enzymes. Our results suggest that NMR has more efficient BER and NER systems than the short-lived and tumor-prone mouse, which may contribute to longevity and cancer resistance of this species.

Late Life IGF-1 Inhibition Modestly Extends Life in Female Mice Only

One of the most studied areas of metabolism and its interaction with aging involves the activities of, and relationships between, IGF-1, insulin, growth hormone, and their cell surface receptors, all of which are among the mechanisms strongly influenced by calorie restriction. Genetic engineering to disable growth hormone or its receptor produces dwarf mice that live 60% longer, and IGF-1 can be similarly manipulated to produce a less exceptional life extension. It is worth noting that the equivalent growth hormone loss of function mutants in our species do not live 60% longer, though they may be modestly more resistant to age-related disease. Short-lived species have evolved a far greater plasticity of life span in response to calorie restriction or interventions that directly manipulate the related cellular mechanisms. Development of therapies based upon these findings seem unlikely to produce sufficiently sizable effects on human health to justify the investment, given the range of better alternatives on the table.

Diminished growth hormone (GH) and insulin/insulin-like growth factor-1 (IGF-1) signaling extends lifespan in many laboratory models. Likewise, several dwarf models, including Ames, Snell and growth hormone receptor knockout (GHRKO) mice, are exceptionally long lived. A specific role for IGF-1 receptor (IGF-1R) signaling in the mediation of mammalian longevity was first established in IGF-1R haploinsufficient mice, which lived 33% longer than controls, but unlike other models of reduced somatotropic signaling, this effect was female specific. This unique sex difference was subsequently confirmed in two follow-up studies, though with more modest reported improvements in female lifespan, while a life shortening effect was observed in males. The underlying mechanisms linking reduced IGF-1 signaling to improved mammalian lifespan is thought to involve improved stress defenses and lower risk for proliferative diseases, though the reason for sex differences in this response remains unresolved.

Several examples have also now emerged suggesting the GH/IGF-1 signaling pathway is relevant to human aging, including the discovery of functional mutations in the IGF-1R gene in individuals with exceptional longevity, resulting in relative IGF-1 resistance, and in subjects lacking functional GH receptors (Laron dwarfs). Remarkably, low IGF-1 levels also predict better survival in nonagenarians, and similar to lessons learned in IGF-1R heterozygous mice, this effect is female specific. Thus, given the accumulating evidence across species implicating this pathway as integral to aging and its associated diseases, the development of therapeutics aimed at modulating IGF-1 signaling in humans could prove highly effective as a translational tool to delay aging. However, given that previous demonstrations of longevity resulting from disruption of this pathway occurred either at conception or in young adulthood, whether benefits can be achieved by targeting this pathway later in life is unclear.

Anti-IGF-1 receptor (IGF-1R) monoclonal antibodies (mAbs) were developed for clinical use in treating advanced stage cancers. We postulated that IGF-1R mAbs could represent a viable therapeutic tool to target IGF-1 action, and potentially mimic the beneficial effects associated with diminished IGF-1 signaling observed in animal models. In order to test this possibility, we engineered a murinized version of the anti-IGF-1R mAb, L2-C (L2-Cmu), in order to reduce effector function and enable chronic administration in mice. L2-Cmu proved feasible and well tolerated in older animals, and consistent with genetic models of IGF-1R heterozygosity, improves female healthspan and increases median lifespan by 9%. Importantly, these effects were achieved even though treatment was not initiated until 18 months of age. Thus, these data suggest that late-life targeting of IGF-1R signaling can recapitulate effects observed in genetic models of constitutive IGF-1R haploinsufficiency on lifespan. As IGF-1R mAbs are readily available for human use, these observations warrant further study into potentially harnessing these drugs to target at least some manifestations of aging.

A First Pass at Artificial Cell Structures Capable of Influencing the Immune System

I think it a little much to be calling the artificial cell structures reported here T cells; the similarities are few. They are pseudo-cell-like membranes that can be decorated with surface features capable of interacting with other cell populations. The goal touted here is to influence the immune system, but in principle any sort of cell to cell communication that relies on surface decoration could be targeted in this way. Being able to build membranes that can pass for cells in the body, and thus avoid the attention of the immune system, seems more useful for the ability to hide molecular machinery inside them, however. Plasmids that can generate specific proteins, for example - a great deal might be accomplished with the ability to introduce durable protein factories into a specific tissue.

Researchers have developed synthetic T lymphocytes, or T cells, that are facsimiles of human T cells. Such cells could eventually be used to boost the immune system of people with cancer or immune deficiencies. Natural T cells are difficult to use in research because they're very delicate, and because after they're extracted from humans and other animals, they tend to survive for only a few days. "We were able to create a novel class of artificial T cells that are capable of boosting a host's immune system by actively interacting with immune cells through direct contact, activation, or releasing inflammatory or regulatory signals. We see this study's findings as another tool to attack cancer cells and other carcinogens."

The team fabricated T cells using a microfluidic system. They combined two different solutions - mineral oil and an alginate biopolymer, a gum-like substance made from polysaccharides and water. When the two fluids combine, they create microparticles of alginate, which replicate the form and structure of natural T cells. The scientists then collected the microparticles from a calcium ion bath, and adjusted their elasticity by changing the concentration of calcium ions in the bath.

Once they had created T cells with the proper physical properties, the researchers needed to adjust the cells' biological attributes - to give them the same traits that enable natural T cells to be activated to fight infection, penetrate human tissue, and release cellular messengers to regulate inflammation. To do that, they coated the T cells with phospholipids, so that their exterior would closely mimic human cellular membranes. Then, using a chemical process called bioconjugation, the scientists linked the T cells with CD4 signalers, the particles that activate natural T cells to attack infection or cancer cells.

Unity Biotechnology Starts First Human Trial of a Senolytic Therapy

The honor of running the first trial of a senolytic drug, albeit inadvertently, goes to one of the groups testing dasatinib or navitoclax back when those pharmaceuticals were first evaluated for cancer therapies. At that time nobody knew that these drugs could selectively destroy senescent cells, and were thereby far more valuable as a starting point for rejuvenation therapies than as cancer treatments. The first intentional human trial was started last year by Betterhumans, a non-profit organization. Now Unity Biotechnology has recently announced that their first human trial is underway, testing the ability of their initial candidate senolytic to treat osteoarthritis. You may recall that the evidence in animal models for the accumulation of senescent cells to be a primary cause of osteoarthritis is fairly compelling. We can hope that this holds up in humans; results will likely start to appear in a preliminary form next year.

UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to extend healthspan by slowing, halting, or reversing diseases of aging, today announced the treatment of the first patient in the Phase 1 clinical trial evaluating UBX0101 in moderate to severe osteoarthritis of the knee. "For many people, we believe that osteoarthritis is the main reason why it hurts to get old. By designing a treatment to selectively eliminate senescent cells in the joints of patients diagnosed with painful osteoarthritis, our goal is to alter the otherwise disabling course of this disease. This is an important milestone for UNITY. This is the first time we have treated a patient with a drug to eliminate senescent cells. While this study is designed to establish safety, we are also looking for the earliest signals of reducing senescent cell burden in this disease of aging."

The Phase 1 clinical trial of UBX0101 is a randomized, double-blind, placebo-controlled, single ascending dose study that will evaluate safety, tolerability, and pharmacokinetics of a single intra-articular injection of UBX0101 in patients diagnosed with moderate to severe osteoarthritis of the knee. Patients will be randomly assigned to receive UBX0101 or placebo in 3:1 randomization by dose level cohort.

Cellular senescence is a natural biological state in which a cell permanently halts division. Senescent cells accumulate with age and secrete as many as 100 different biologically active proteins, including pro-inflammatory factors, proteases, pro-fibrotic factors, and growth factors that disturb the tissue microenvironment. This collection of secreted proteins is referred to as the Senescence Associated Secretory Phenotype, or SASP. In addition to its effects on tissue function, the SASP contains factors that induce senescence in neighboring cells, setting off a cascade of events that culminates in the formation of the functionally aged and/or diseased tissue that appears to underlie a variety of age-associated diseases. UNITY believes that the elimination of senescent cells will remove SASP factors - addressing a root cause of diseases of aging. Senolytic medicines, or treatments designed to selectively remove senescent cells, target the SASP at its source, and may have a more durable impact on disease than current therapies.

Interfering in an Amplification Loop for Oxidative Stress in Aging Mice

Researchers here report on the identification of a mechanism in mice that amplifies the harms done by an excess of oxidative molecules. Aging is accompanied by a general increase in oxidative stress in cells, and suppressing this amplication mechanism is shown to improve measures of health and slow the progression of aspects of aging. This is similar in spirit to a number of other lines of research that seek to attenuate oxidative stress in old tissue, such as the use of mitochondrially targeted antioxidants, but tackling the challenge at a completely different point of action. Arguably none of this addresses root causes: rising levels of oxidative stress are a consequence of lower level forms of damage and change in aging. So we should expect the scope of benefits to be limited; the results of mitochondrially targeted antioxidants in flies and mice over the past decade might set the expected ballpark.

Aging is characterized by a number of physiological changes including loss of cell division, oxidative stress, DNA damage, nuclear changes, and increased expression of senescence-associated genes. It has been known for some time that oxidant stress plays a central role in the aging process, and is causally involved in the injury to cellular proteins and DNA. When reactive oxygen species (ROS) accumulation exceeds the detoxifying ability of the cell, the resulting oxidative stress induces damage, senescence, and apoptosis.

We recently reported that the Na/K-ATPase - Src - EGFR signaling pathway serves as a feed-forward amplification loop for oxidants (Na/K-ATPase oxidant amplification loop, NKAL), a signaling cascade resulting in additional ROS generation. We further showed that this NKAL is involved in various disease models ranging from uremic cardiomyopathy to obesity. Our group developed a peptide, pNaKtide, from the N domain of the Na/K-ATPase α1 subunit. This peptide binds Src kinase; ultimately inhibiting the Na/K-ATPase feed forward amplification of ROS. Based on these earlier observations, we hypothesized that the NKAL might play a role in the aging process and antagonism of this pathway by pNaKtide might attenuate the aging process.

We previously showed that a western diet (WD) induced Na/K-ATPase signaling and increased oxidative stress in mice. We used this dietary approach to investigate the effects of age and oxidative stress in adipose tissue, and heart, which are both affected by the aging processes. In both of these organ systems, old mice and old mice fed a WD had evidence for oxidant injury, which was related to the stimulation or inhibition of the NKAL with the WD or pNaKtide, respectively. In our experiments, old mice had increased fat deposition along with large adipocytes and increased TNFα levels; these changes were accentuated in the old mice fed a WD. Aging of heart tissues is associated with impaired function detectable with echocardiography and fibrosis measurable with histology. These changes were exacerbated by the WD and attenuated by pNaKtide treatment as well. Again, these changes in adipose tissues were negated with pNaKtide treatment.

Back to Arguing for a Mortality Rate Plateau in Extremely Old Humans

I'm of the opinion that there simply isn't enough data on extremely old humans to do more than roll the dice on the outcome produced by any one statistical analysis, though the results noted here are based on a large enough study population to perhaps demand more attention than past efforts. The researchers have avoided the very sparse data for supercentenarians (110 and older) by focusing on people aged 105 to 110. They conclude that mortality rates stay much the same across that span, at more or less a 50% yearly attrition. This disagrees with one of the more recent attempts to run the numbers for supercentenarian mortality rates.

Aging is defined as the increase of intrinsic mortality rate over time, and a lack of increase is therefore classed as functional immortality by some researchers. Not the useful, desirable sort of immortality, of course. This phenomenon has good supporting data in flies, a species that readily exhibits a late life mortality rate plateau. Whether this happens in mammals, and particularly in humans, is much debated. There are arguments on both sides. It is interesting to ponder whether this functional immortality represents only a temporary buffer in the state of a few critical systems, or would instead continue for much longer, were there enough data to follow mortality that far into physiological loss of function.

The answers may never be known. It is unlikely that many times more physiologically extremely old people than exist today will ever exist. Rejuvenation therapies will emerge over the decades ahead as a counterpoint to demographic aging. The natural state of aged humanity, the fate of everyone absent the ability to repair the root causes of aging, will come to an end. Whether the few survivors at the end of a natural lifetime are strangely immortal will be a question for future computational scientists and their advanced models, not future demographers. Given the lack of interest in modeling exact outcomes of extinct disease states today, I'm not convinced that future scientific and funding communities will care enough to investigate.

Researchers tracked the death trajectories of nearly 4,000 residents of Italy who were aged 105 and older between 2009 and 2015. They found that the chances of survival for these longevity warriors plateaued once they made it past 105. The findings challenge previous research that claims the human lifespan has a final cut-off point. To date, the oldest human on record, Jeanne Calment, died in 1997 at age 122. "Our data tell us that there is no fixed limit to the human lifespan yet in sight. Not only do we see mortality rates that stop getting worse with age, we see them getting slightly better over time."

Specifically, the results show that people between the ages of 105 and 109, known as semi-supercentenarians, had a 50/50 chance of dying within the year and an expected further life span of 1.5 years. That life expectancy rate was projected to be the same for 110-year-olds, or supercentenarians, hence the plateau. The trajectory for nonagenarians is less forgiving. For example, the study found that Italian women born in 1904 who reached age 90 had a 15 percent chance of dying within the next year, and six years, on average, to live. If they made it to 95, their odds of dying within a year increased to 24 percent and their life expectancy from that point on dropped to 3.7 years.

The researchers used data from the Italian National Institute of Statistics. They credit the institute for reliably tracking extreme ages due to a national validation system that measures age at time of death to the nearest day: "These are the best data for extreme-age longevity yet assembled." As humans live into their 80s and 90s, mortality rates surge due to frailty and a higher risk of such ailments as heart disease, dementia, stroke, cancer, and pneumonia. Evolutionary demographers theorize that those who survive do so because of demographic selection and/or natural selection. Frail people tend to die earlier while robust people, or those who are genetically blessed, can live to extreme ages.


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