Fight Aging! Newsletter, April 3rd 2017

As the population is aging, the incidence of age-related neurodegenerative diseases, such as Alzheimer and Parkinson disease, is growing. The pathology of neurodegenerative diseases is characterized by the presence of protein aggregates of disease specific proteins in the brain of patients. Under certain conditions these disease proteins can undergo structural rearrangements resulting in misfolded proteins that can lead to the formation of aggregates with a fibrillar amyloid-like structure. The role of these aggregates in disease is not fully understood: the most prevalent hypothesis is that aggregation intermediates - single or complexes of aggregation-prone proteins - are toxic to cells and that the aggregation process represents a cellular protection mechanism against these toxic intermediates.

Cells have a protein quality control (PQC) system to maintain protein homeostasis. Preserving protein homeostasis involves the coordinated action of several pathways that regulate biogenesis, stabilization, correct folding, trafficking, and degradation of proteins, with the overall goal to prevent the accumulation of misfolded proteins and to maintain the integrity of the proteome.

One of the cellular mechanisms that copes with misfolded proteins is the chaperone machinery. A molecular chaperone is defined as a protein that interacts with, stabilizes or assists another protein to gain its native and functionally active conformation without being present in the final structure. In addition to folding of misfolded proteins, molecular chaperones are also involved in a wide range of biological processes such as the folding of newly synthesized proteins, transport of proteins across membranes, macromolecular-complex assembly or protein degradation and activation of signal transduction routes. Next to their function under normal cellular conditions, chaperones play an important part during neurodegeneration when there is an overload of the PQC system by unfolded proteins. Each neurodegenerative disease is associated with a different subset of chaperones such as heat shock proteins that can positively influence the overload of unfolded proteins

Protein degradation is another key mechanism to deal with misfolded proteins. Three pathways have been described, i.e., the ubiquitin-proteasome system (UPS), chaperone mediated autophagy (CMA), and macroautophagy. Protein aggregates or proteins that escape the first two degradation pathways are directed to macroautophagy, a degradation system where substrates are segregated into autophagosomes which in turn are fused with lysosomes for degradation into amino acids. The proteins involved in neurodegenerative disease can rapidly aggregate and can thereby escape degradation when they are still soluble, the aggregates and intermediate forms are partly resistant to the known degradation pathways.

A further compensatory mechanisms involves the endoplasmic reticulum (ER). The unfolded protein response (UPR), induced during periods of cellular and ER stress, aims to reduce unfolded protein load, and restore protein homeostasis by translational repression. ER stress can be the result of numerous conditions, including amino acid deprivation, viral replication and the presence of unfolded proteins, resulting in activation of the UPR. In addition, misfolded proteins can be sequestered in distinct protein quality control compartments in the cell by chaperones and sorting factors. These compartments function as temporary storage until the protein can be refolded or degraded by the proteasome. Different compartments have been described in the literature that sequester different kind of misfolded proteins at various conditions.

Under normal conditions, the PQC can rapidly sense and correct cellular disturbances by activating stress-induced cellular responses to restore the protein balance. During aging or when stress becomes chronic, the cell is challenged to maintain proper protein homeostasis. Eventually, this can lead to chronic expression of misfolded and damaged proteins in the cell that can result in the formation of protein aggregates. The presence of aggregation-prone proteins contributes to the development of age-related diseases. The decline of protein homeostasis during aging is a complex phenomenon that involves a combination of different factors. In line with the decreased protein homeostasis, there appears to be an impairment of the upregulation of molecular chaperones during aging. Since all major classes of molecular chaperones, with the exception of the small heat shock proteins, are ATPases it has been suggested that the depletion of ATP levels during aging due to mitochondria dysfunction would affect their activity. This is reflected by the repression of ATP-dependent chaperones and the induction of ATP-independent chaperones in the aging human brain. This may contribute to the decline of chaperoning function during aging.

Under the right conditions any protein could form amyloid-like structures. Although amyloids have been traditionally related to diseases, they also have diverse functions in organisms from bacteria to human that may underlie their nature. Nevertheless, the toxicity of amyloid intermediate species associated with disease makes protein aggregation a process that has to be under tight control and regulation. In this context, aging is a key risk factor due to the progressive decline of protein homeostasis, which leads to increased protein misfolding and aggregation. This can eventually result in the onset of age-related diseases characterized by protein aggregation. As the human population becomes older, it is essential to understand the processes underlying age-related diseases that are the result of protein aggregation and its associated toxicity. This is a very broad research field, ranging from biophysics to clinical trials. Every year discoveries are made that involve the identification of factors affecting protein aggregation. It can be concluded that the overall knowledge of the aggregation process is improving, which will allow for the development of new and accurate treatments against aggregation-linked diseases.

The overall effects of ionizing radiation on organisms are well known at high doses. At high and low doses, the detailed cell response mechanisms are complicated and may involve all levels of biological organization. About 75% of the human body is water, and a principal effect of radiation is the creation of reactive oxygen species (ROS), including hydrogen peroxide. They are a double-edged sword. Depending on their concentrations, they may cause damage or signaling in terms of stress responses. Studies on experimental living systems and on humans have shown, depending on the individual genome, that low doses of radiation upregulate many biological protective mechanisms, which also operate against nonradiogenic toxins and produce beneficial effects, including a lower risk of cancer.

For more than a century, extensive studies have been carried out on the effects of radiation, which demonstrate that harmful effects, such as radiation illness, may arise after exposures above known threshold dose levels, whereas a range of beneficial effects may be observed following low-dose exposures. Although there appears to be an awareness among the prominent leaders of the radiation protection establishment that current radiation protection policy contradicts this biological evidence; there is a very broad consensus among them that it is impossible to attribute health effects to low radiation exposures, namely to exposures similar to the wide spectrum of background levels. This opinion does not consider the recent progress in biological research on the mechanisms that underlay the fact that living organisms are "complex adaptive systems."

When people increasingly question whether low levels or low doses of radiation are really harmful, protection practitioners argue that "radiation-sensitive individuals" exist who are more vulnerable than average people to potential "health effects" and must be protected. This concern about protecting sensitive individuals and the suggestion that longevity may be the most appropriate measure of the effect of radiation on health led to this examination of the effect of dose rate on the lifespans of dogs. The authors reexamined data on the health effects of long-term irradiations in two large-scale studies on groups of beagle dogs. One exposed the dogs to whole-body cobalt-60 γ-radiation. The other evaluated dogs whose lungs were exposed to α-particle radiation from plutonium. Each group of dogs received a different dose rate.

These studies had been reviewed previously to determine the dependence of the lifespan of 50% mortality dogs on dose rate. The lifespans of dogs at 5%, 10%, and 50% mortality in the control group (background dose rate) were compared with the lifespans of the 5%, 10%, and 50% mortality dogs in each dose rate group. Analysis of the data of the first study suggested an increase in the lifespan of dogs exposed to 50 mGy of γ-radiation per year, compared to the control dogs. Analysis of the data of the second study suggested an increase in longevity for dogs with an initial plutonium lung burden of 0.1 kBq/kg, compared to the control dogs. These are very credible studies, carefully carried out by qualified and experienced scientists who bred the dogs and controlled all confounding factors. Interpolations of the study data suggest that the optimum dose rate for longevity is about 50 mGy per year for all mortality levels. The lifespan increase is about 15% for 50% mortality dogs and much greater for the more radiation-sensitive dogs. The shorter lived control dogs (5% mortality level) have a lifespan of about 3000 days, whereas the dogs in the group with an initial plutonium lung burden of 0.16 kBq/kg have a lifespan of about 4500 days, 50% longer.

If dogs model humans, then one should expect that radiation-sensitive individuals would benefit more from exposures to low-level radiation than average humans. So protecting sensitive people from low-dose γ- or α-radiation would be inappropriate because it would deprive them of the health benefit of a longer life. The results of this review suggest the need to change radiation protection policy. Obviously, maintaining exposures as low as reasonably achievable is very likely detrimental.

The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Autophagy and the DNA damage response (DDR) are biological processes essential for cellular and organismal homeostasis. Herein, we summarize and discuss emerging evidence linking DDR to autophagy. We highlight published data suggesting that autophagy is activated by DNA damage and is required for several functional outcomes of DDR signaling, including repair of DNA lesions, senescence, cell death, and cytokine secretion. Uncovering the mechanisms by which autophagy and DDR are intertwined provides novel insight into the pathobiology of conditions associated with accumulation of DNA damage, including cancer and aging, and novel concepts for the development of improved therapeutic strategies against these pathologies.

Autophagy is emerging as one of the core orchestrators of healthy aging. This self-degradation process is present in all mammalian cells and tissues, including the central nervous system (CNS), and specializes in directing unnecessary or damaged intracellular material to the lysosome, the major cellular organelle that digests and recycles all types of macromolecules. Autophagy, as a constitutive mechanism, participates in the basal turnover of long-lived proteins and organelles, playing a major role as a checkpoint for quality control. On the other hand, stressful situations such as metabolic starvation or functional damage induce an adaptive autophagic response to restore cellular homeostasis. Thus, adaptive autophagy provides the cell with nutrients and energy during metabolic shortage and relieves it from toxic components during functional damage. Accordingly, a correct completion of the autophagic response is central for optimal CNS physiology and the promotion of neuronal survival. This is evidenced by the elevated number of connections made between the dysregulation of autophagy, aging, and neurodegeneration.

In this review, we will describe the role of autophagy (dys)regulation in the aged and diseased brain. Particularly, we will focus on microglia, the brain's resident macrophages with intrinsic capability to respond to CNS damage, promoting repair and a correct brain function. First, we will briefly outline the process of autophagy and its regulation, and summarize key technical aspects for the correct monitoring of autophagy at the experimental level. Then we will review the role of autophagy in neurons and the impact of autophagy failure in neurodegeneration. Finally, we will detail the current state of the literature on the role of autophagy in peripheral macrophages and microglia, including the regulation of phagocytosis and the inflammatory response.

Starting on March 29th in Kotor, Montenegro, the first Longevity School is being held, organized by the patients' organization Open Longevity. The purpose of our organization is to carry out clinical trials of therapies against aging. We are determined to create the best possible therapies based on all achievements of science and considering individual approach. Recently we've started to organize clinical trials of a new type, based on the principles of openness, with a non-commercial approach, and aiming for continuous improvement of the effectiveness of interventions under trial. We believe that by not focusing on opportunities to capitalize the cure for old age, and by immediately publishing the results of clinical experiments, we will achieve a higher level of expertise. The protection of scientific advances by patents and trial data by secrecy leads to a lack of exploration of the potential reuse of existing therapies for new purposes, since it is impossible to ensure sufficient freedom to use the results.

The first task of the Longevity School in Montenegro is to raise the level of knowledge of the participating patients. For this matter, we will conduct 67 lectures on the biology of aging with a final exam. Our goal is to establish cooperation, a dialogue between patients, doctors, and scientists to achieve the common goal of radical life extension. Second, we will start testing a fasting mimicking diet, which aims to reduce the level of insulin-like growth factor 1 in humans. The third step is the preparation of clinical trials protocols for testing combinations of anti-aging interventions. We will have five roundtable discussions to come up with the best strategy. In doing so, our goal is not just to confirm or deny effectiveness of a drug or a combination of drugs. We will not stop at testing of a minor drug candidate like metformin. Our goal is to constantly increase the power of interventions, adapting it to the current situation and health conditions. That is why one of the tasks for Open Longevity project is to implement aging diagnostics into clinical practice.

The first Longevity School will be held from 29 March to 7 April. The Montenegro school is our first one, but we will systematically run Longevity Schools on all continents to engage millions of people into the common cause of life extension. We are moving from simple to complex, from diet to gene therapy, until aging is defeated.

C4 Therapeutics (C4T) and Calico today announced a five-year collaboration to discover, develop, and commercialize therapies for treating diseases of aging, including cancer. Under the terms of the agreement, the parties will leverage C4T's expertise and capabilities in targeted protein degradation to jointly discover and advance small molecule protein degraders as therapeutic agents to remove certain disease-causing proteins. The partnership will pursue preclinical research and Calico will be responsible for subsequent clinical development and commercialization of resulting products that may emerge from the collaboration.

"We know from decades of translational research that it can be incredibly challenging to find effective pharmacologic inhibitors of many of the biologically well-validated targets, particularly in cancer. Through the alternative strategy of specifically targeting such proteins for degradation, we believe we have the opportunity to identify promising new therapeutics in cancer and in other diseases as well. We're looking forward to collaborating with C4T's scientists and applying their protein degradation technology to the discovery and development of effective new treatments."

C4 Therapeutics is a private biotechnology company developing a new class of drugs based on Targeted Protein Degradation (TPD) to address a broad range of life-threatening and life-impairing diseases. C4T's platform uses small molecule drugs to direct the machinery of the ubiquitin-proteasome system to selectively degrade disease-relevant proteins for therapeutic benefit. This distinctive mechanism provides new opportunities to target traditionally difficult-to-treat diseases and diseases plagued by drug resistance.

Mammalian aging is characterized by a gradual decline of numerous health parameters with multiple biochemical, physiological and behavioral manifestations. Several animal models have been successfully used over the last several decades to address mechanistic aspects of aging and development of age-related diseases. In most of these studies the major metric parameter for assessing pro-/anti-aging effect of genetic, nutritional or pharmacological manipulation has been the animals' lifespan. While being informative, longevity by itself however, cannot provide an assessment of the animal's health status, which, like in humans, can significantly decline at older ages and therefore reduce the quality of life. This concern is particularly relevant to research focused on developing the "healthspan"-extending pharmaceuticals, efficacy of which may not be necessarily translated in increased longevity but rather in prolongation of healthy life and require quantitative objective assessment.

Clinical studies in humans measure age-related declines in performance by quantifying the frailty index (FI), which reflects accumulation of health deficits during chronological aging. Since numerous studies have shown that many age-associated changes that occur in humans are also present in aged mice, FI was recently introduced as a measure of mouse aging to pre-clinical models. However, standardized and comprehensive approaches for FI measurements, which will address changes in a broad spectrum of physiological functions, are still missing. Here we describe the development of an alternative scoring system, based on a selected set of non-invasive quantitative and physiological parameters, which could be repetitively used in the same animal over the course of its entire lifespan. We refer to this set of parameters as physiological frailty index (PFI). After measuring 29 diverse parameters including physical (body weight and grip strength), blood cell composition, metabolic, and immune properties, we selected those that show statistically significant change with age. These parameters were used to create PFI of individual mice of different chronological age. The observed gradual increase in mean PFI values with age suggests that our approach can reliably detect the scale of age-dependent health deterioration in a quantitative manner.

We also validated our approach of PFI by testing detrimental (feeding high fat diet, HFD) and beneficial (treatment with mTOR inhibitor rapamycin) factors on animals' longevity. We demonstrated acceleration of growth of PFI in animals placed on a high fat diet, reflecting aging acceleration by obesity. Additionally, we showed that PFI could reveal the anti-aging effect of mTOR inhibitor rapatar (a bioavailable formulation of rapamycin) prior to registration of its effects on longevity. PFI also revealed substantial sex-related differences in normal chronological aging and in the efficacy of detrimental (high fat diet) or beneficial (rapatar) aging modulatory factors.

For decades, the solution to aging has seemed merely decades away. In the early nineties, research on C. elegans, a tiny nematode worm that resembles a fleck of lint, showed that a single gene mutation extended its life, and that another mutation blocked that extension. The idea that age could be manipulated by twiddling a few control knobs ignited a research boom, and soon various clinical indignities had increased the worm's life span by a factor of ten. Death would no longer be a metaphysical problem, merely a technical one. The celebration was premature. Gordon Lithgow, a leading C. elegans researcher, told me, "At the beginning, we thought it would be simple - a clock! - but we've now found about five hundred and fifty genes in the worm that modulate life span. And I suspect that half of the twenty thousand genes in the worm's genome are somehow involved."

For us, aging is the creeping and then catastrophic dysfunction of everything, all at once. Our mitochondria sputter, our endocrine system sags, our DNA snaps. Our sight and hearing and strength diminish, our arteries clog, our brains fog, and we falter, seize, and fail. Every research breakthrough, every announcement of a master key that we can turn to reverse all that, has been followed by setbacks and confusion. A few years ago, there was great excitement about telomeres, DNA buffers that protect the ends of chromosomes just as plastic tips protect the ends of shoelaces. As we age, our telomeres become shorter, and, when these shields go, cells stop dividing. If we could extend the telomeres, the thinking went, we might reverse aging. But it turns out that animals with long telomeres, such as lab mice, don't necessarily have long lives - and that telomerase, the enzyme that promotes telomere growth, is also activated in the vast majority of cancer cells. The more we know about the body, the more we realize how little we know.

In the murk of scientific inquiry, every researcher looks to a ruling metaphor for guidance. Aubrey de Grey likes to compare the body to a car: a mechanic can fix an engine without necessarily understanding the physics of combustion, and assiduously restored antique cars run just fine. De Grey is the chief science officer of Silicon Valley's SENS Research Foundation, which stands for Strategies for Engineered Negligible Senescence - a fancy way of saying "Planning Your Comprehensive Tune-up." De Grey has proposed that if we fix seven types of physical damage we will be on the path to living for more than a thousand years. "Gerontologists have been led massively astray by looking for a root cause to aging, when it's actually that everything falls apart at the same time, because all our systems are interrelated. So we have to divide and conquer." We just need to restore tissue suppleness, replace cells that have stopped dividing and remove those that have grown toxic, avert the consequences of DNA mutations, and mop up the gunky by-products of all of the above. If we can disarm these killers, de Grey suggests, we should gain thirty years of healthy life, and during that period we'll make enough further advances that we'll begin growing biologically younger. We'll achieve "longevity escape velocity."

De Grey vexes many in the life-extension community with his prophetic air of certainty. His 2007 book, "Ending Aging," is replete with both exacting research into the obstacles to living longer and proposed solutions so ambitious that they resemble science fiction. De Grey's fix for mitochondrial mutation, for instance, is to smuggle backup copies of DNA from the mitochondria into the vault of the nucleus, which evolution annoyingly failed to do-probably because the proteins needed in the mitochondria would ball up during their journey through the watery cell body. His fix for that, moving the DNA one way and the proteins that it produces another, amounts to a kind of subcellular hokey pokey. A number of scientists praise de Grey for anatomizing the primary threats, yet they see troubleshooting all seven pathways through such schemes - and you have to troubleshoot them all for his plan to work - as a foredoomed labor. Biogerontologist Matt Kaeberlein said, "It's like saying, 'All we have to do to travel to another solar system is these seven things: first, accelerate your rocket to three-quarters of the speed of light... ' "

Ned David is a biochemist and a co-founder of a Silicon Valley startup called UNITY Biotechnology. UNITY targets senescent cells - cells that, as they age, start producing a colorless, odorless, noxious goo called SASP, which UNITY's researchers call "the zombie toxin," because it makes other cells senescent and spreads chronic inflammation throughout the body. In mice, UNITY's treatments delay cancer, prevent cardiac hypertrophy, and increase median life span by thirty-five per cent. "We think our drugs vaporize a third of human diseases in the developed world." Pharma and biotech companies make money only if they treat a disease, and, because aging affects everything, the FDA doesn't recognize it as an "indication" susceptible to treatment (or to insurance-company reimbursement). So UNITY is taking aim at glaucoma, macular degeneration, and arthritis.

Senescent cells accumulate with age in a wide range of tissues. The rate of accumulation of senescent cells in liver and intestinal crypts predicts median and maximum lifespan of mice in cohorts with widely different aging rates. More importantly, interventions that selectively ablate senescent cells by genetic and/or pharmacologic means may improve healthspan and lifespan in mice. Mechanistically, the age-promoting effects of senescence are associated with the restriction of regenerative capacity of stem and progenitor cells as well as the secretion of bioactive molecules (the so-called senescence-associated secretory phenotype, SASP), specifically pro-inflammatory and matrix-modifying peptides. Pro-aging effects of senescent cells are aggravated by SASP and, possibly, other paracrine mediators which can propagate senescence from cell to cell as a bystander effect. In recent years, evidence has been mounting that senescent cells impact on their environment via yet another principal pathway: mitochondrial dysfunction.

Along with cell senescence, mitochondrial dysfunction is another essential 'hallmark of aging', and the two have been independently identified as important drivers of aging. Importantly, they are closely interlinked: mitochondrial dysfunction drives and maintains cell senescence, while at the same time cell senescence, specifically persistent DNA damage response signalling, directly contributes to Senescence-Associated Mitochondrial Dysfunction (SAMD). Despite the close interdependent relationship between senescence and SAMD, the true complexity of these interactions and their role in aging remains to be elucidated. For example, it is currently unclear how much of the mitochondrial dysfunction that has been observed at tissue level during aging is actually associated with senescence at a cellular level. Furthermore, despite its central contribution to the senescent phenotype, it is not clear how mitochondria become dysfunctional in senescence.

An important question is to what extent aging-associated mitochondrial dysfunction and cell senescence/SAMD are interrelated. Does aging-related mitochondrial dysfunction cause senescence in vivo or vice versa? Is mitochondrial dysfunction in aging actually a mosaic phenomenon, occurring preferentially or exclusively in the senescent cells? Given the high prevalence of senescent cells in many tissues, this appears highly possible. Emerging data suggest that it is SAMD rather more than general loss of mitochondrial function in aging that reduces homeostatic capability, causing compromised responses to peak energy demand and driving metabolic insufficiency in aging. For instance, we have found that SAMD in hepatocytes (and other cell types) includes a compromised capacity to metabolize fatty acids, which causes lipid storage in aging liver and thus contributes to fatty liver (steatosis), a common and pathologically significant complication of liver aging. Adipocyte senescence is an essential driver of adipose tissue dysfunction and obesity, and this link is very probably mediated by SAMD. Analysing mitochondrial dysfunction in aging tissues at single-cell resolution in combination with interventions that selectively ablate senescent cells will enable a better understanding of the importance of SAMD in aging.

Can a pill make you younger? One of the few drug studies ever carried out in an attempt to address this question was reported by Novartis on Christmas Eve 2014. The company had sought to see whether giving low doses of a drug called everolimus to people over 65 increased their response to flu vaccines. It did, by about 20 percent. Yet behind the test was a bigger question about whether any drug can slow or reverse the symptoms of old age. Novartis's study on everolimus, which looked at whether the immune system of elderly people could be made to act younger, has been called the "first human aging trial."

Last week a Boston company, PureTech Health, said it was licensing two drug molecules, and the right to use them against aging-related disease, from Novartis and making the research the basis of a startup company, resTORbio. The company says it will further test whether such drugs can rejuvenate aged immune cells. The drug Novartis tested is a derivative of rapamycin, a compound first discovered oozing from a bacterium native to Easter Island, or Rapa Nui, and named after it. Thanks to its broad effects on the immune system, rapamycin has already been used in transplant medicine as an immune suppressant.

What's even more interesting about rapamycin, however, is its reputation as the most consistent way to postpone death, at least in laboratory species. It lengthens the lives of flies, worms, and rodents, too. Feed the compound to mice and they live 25 percent longer, on average. A study is under way in Seattle to see if rapamycin extends the lives of pet dogs. What we don't have yet are formal studies of whether rapamycin or any other drug can lengthen people's life spans. For many reasons, companies haven't been keen to pursue potential anti-aging treatments. Scientifically, longevity pills remain an outré idea, the domain of cranks and quacks. Clinically, it's difficult to prove a drug extends life, as it would take too long. Regulation-wise, there's no clear path forward, as aging hasn't generally been recognized as a disease you can treat. But recently, venture capitalists who used to run from such ideas have begun investing.

Brian Kennedy, who researches aging at the Buck Institute, says the Novartis study was "groundbreaking" because of how it found a way to address the drug's impact on the effects of age. "No one has the stomach to do longevity studies. Or you can do what Novartis did, which is to choose a property of aging and see if you can slow it down." Novartis says it will soon be reporting more results from its studies in the elderly. But the company also decided that the research did not fit its priorities. "We will stop developing it for aging-related disorders. It's outside of our current strategy." The resTORbio startup will try to use the Novartis drugs to reverse what it calls "immunosenescence," or detrimental changes to the immune system that occur with age. In part, that might include trying to restore certain types of T cells, which become exhausted and don't remain vigilant against cancer and infections.

Aging at the cellular level is called "cell senescence", and it contributes profoundly to whole-body aging. The most promising near-term prospects for a leap in human life expectancy come from drugs that eliminate senescent cells. Programs in universities and pharmaceutical labs around the world are racing to develop "senolytic" drugs, defined as agents that can kill senescent cells with minimal harm to normal cells.

By analogy with chemotherapy for cancer, the value of a senolytic treatment is measured by its ability to kill senescent cells without doing harm to normal cells. The index called SI50 (SI for "selectivity index - 50%") is defined by analogy to LD50, the "lethal dose" of a toxin, the dose at which half of all cells die. SI50 is defined as the ratio of LD50 for normal cells and LD50 for senescent cells. It is the concentration of the agent at which half the normal cells die, divided by the concentration at which half the senescent cells die. A recent study in which researchers killed senescent cells by interfering in the crosstalk between FOXO4 and P53 reported an SI50 about 12. My guess is that 12 is an encouraging beginning, but it is not high enough to support a useful therapy.

The encouraging fact is that, at the optimal dose, more than 80% of the senescent cells have succumbed to apoptosis, while the number of eliminated normal cells is still below detection. Unfortunately, senolytic agents studied previously, including dasatinib, quercetin and ATTAC, did not include measurements of SI50 that we might use for comparison. The authors of the FOXO4 study were in a rush to publish. They used a fast-aging strain of mice, and even for these, they did not wait to see survival curves. The indicatators of rejuvenation that they do report look positive: increased activity levels, regrowth of lost fur, and improvement of kidney function lost with age.

I had missed the two papers about senolytic drug candidates ABT-263 and ABT-737. Both ABT-263 and ABT-737 were identifed in screens for agents that block BCL-2. BCL-2 is the founding member of another family of proteins that signal a cell to resist apoptosis. The ABT-263 paper included some in vivo results, indicating enhanced growth of blood stem cells after senescent cells have been removed. In vivo testing of ABT-737 was limited. Neither group reports the selectivity index (SI50), but from graphs that they do present, it is clear that ABT-263 is more selective than ABT-737, and that neither is as selective as the more recent FOXO4 method.

The idea of removing senescent cells has a lot of appeal, and enjoys broad empirical support in mammals. There is now a world-wide effort, making rapid progress toward specificity in senolytic treatments. The FOXO4 approach involves the newest agent, and it shows the best ratio yet for killing senescent cells while avoiding collateral damage to healthy cells. It cannot be taken orally and must be injected, but perhaps this is not such a drawback for a treatment that is needed only intermittently, every few years. How will such promising mouse results translate into human health and life extension? We have as yet no data, not even anecdotes. But perhaps we are near the point where hope and courage will motivate the first self-experimenting volunteers. This is a fast-moving field in which researchers are in a rush to publish and (presumably) pharmaceutical companies are taking pains to keep their results hushed up. Sharing of information and resources could push this research over the top and give us the first full decade of human life extension.

They may seem rigid and set in their ways, but your bones are actually under constant construction and deconstruction. They give up their nutrient treasures (calcium) to the body and then rebuild in a constant give-and-take sort of rhythm. When that rhythm shifts with advancing age or the onset of osteoporosis, the rebuilding process decreases. Bones lose density and strength and become more prone to fracture. Now researchers have applied mathematical modeling expertise to biological inquiry in order to point the way to a promising remedy. The biologist has shown that treating a mouse with a peptide known as CK2.3 increases bone mineral density. The mathematician has calculated estimated dosages for human beings. According to their model, injections of CK2.3 can raise bone mineral density of bones badly degraded by osteoporosis back to healthy levels.

Bone mineral density is affected by two processes: bone formation and bone degradation. Current drug treatments, especially bisphosphonates, address the cells involved in bone degradation (osteoclasts). Only the approved drug parathyroid hormone (PTH) addresses the cells involved in bone formation (osteoblasts) but doctors must prescribe bisphosphonates with it to target bone degradation simultaneously. The peptide used in this research - CK2.3 - is the only one that decreases bone degradation while simultaneously increasing bone formation.

One team designed the mimetic peptide CK2.3 and showed that it increased bone mineral density in a mouse model by blocking the CK2 protein's interaction with the BMPR1a protein - an interruption that allows the cells that form new bone (osteoblasts) to increase. Subcutaneous (below the skin) injection increased bone formation in the crown of the skull (known as calvaria), while systemic injection decreased bone degradation and increased bone mineral density. The other team used that information to calculate ideal dosages for healthy humans and those with osteoporosis. A mouse and a human are different in many ways, so calculating a dosage is more complex than just adjusting for differences in weight. Researchers developed part of the model using the concepts in physiology-based pharmacokinetic (PBPK) models. Such models can be used to calculate how a pharmaceutical molecule distributes in different parts of the body. In this case, the researchers needed to know what the local concentration of CK2.3 would be at the site where bone is formed. Once this was determined, another math model was used to calculate bone mineral density.

Sarcopenia and decreased cardiac function are common features of the decline in physical performance associated with aging. Sarcopenia refers to a loss of skeletal muscle mass that is accompanied by a decrease in muscle strength and increased fatigue. Aging in the heart is associated with pathological hypertrophy and thickening of the ventricle wall, leading to decreased cardiac output. Changes in both metabolism and macroautophagy, a lysosomal-dependent degradation process, have been associated with aging in both these tissues. These, in turn may contribute to the decline in function observed in these tissues during aging.

Macroautophagy, referred as autophagy in the remainder of this manuscript, is the most studied form of autophagic process. It involves the formation of double-membrane vesicles termed "autophagosomes", the sequestration of cytosolic substrate within autophagosomes, and the subsequent fusion of autophagosome and lysosome to form autophagolysosomes, where the engulfed macromolecules are degraded to provide substrates for cellular metabolism as well as damaged proteins and organelles to maintain cellular homeostasis. There is a tight connection between autophagy and life-span, as genetic manipulation to increase expression of specific autophagy genes in lower organisms promotes longevity. Autophagy-deficient mice also mimic several characteristics of age-related diseases, suggesting that autophagy is a key mechanism for protecting against cellular damage during aging. Furthermore, autophagy is a critical process for maintaining muscle and heart function, and tissue-specific impairment of autophagy in muscle and heart leads to sarcopenia and cardiomyopathy, respectively. Although there is evidence suggesting a potential role of autophagy in aging, the specific changes in basal levels of autophagy in skeletal and cardiac muscle during the natural aging process and the underlying mechanisms have not been well characterized.

Chaperone-mediated autophagy (CMA) is another type of autophagic process that specifically targets proteins that have a KFERQ amino acid recognition sequence for degradation. During CMA, target proteins are first recognized and bound by Hsc70. The resulting complex then is targeted to the lysosomes by binding to the lysosomal CMA receptor LAMP-2A, whereupon the target protein is unfolded and translocated into the lysosome for degradation. A decline of CMA during aging has been reported to occur in both the liver and central nervous system that is associated with decreased function; however, little is known about CMA in other tissues during aging.

Mitochondria are the key organelles for oxidative phosphorylation and ATP production. Mitochondria preferentially use fatty acid or glucose as energy sources depending on the availability of the type of fuel. The fuel selectivity by mitochondria also is subjected to hormonal regulation. During aging, cellular and metabolic stresses can increase generation of reactive oxygen species (ROS) that can damage mitochondria and lead to mitochondrial dysfunction, as well as perturb fuel utilization. Thus, mitochondrial quality control is critical for maintaining normal mitochondrial function and metabolism during aging. This quality control can be achieved by mitochondrial fusion, fission, and/or mitochondrial turnover through removal of damaged mitochondria by autophagy (mitophagy) and concomitant biosynthesis of new mitochondria. Currently, little is known about the changes in mitochondrial quality control and relevant metabolites that occur in aged muscle and heart.

In this study, we systematically examined and compared the markers for autophagy, CMA, and mitochondrial quality control in skeletal and cardiac muscle isolated from young and aged mice, as well as performed metabolomics profiling of acylcarnitines, amino acid and ceramides. Our studies confirm that autophagy declines in both the muscle and heart during aging, although the mechanism for the impairment in autophagy appears to be different between these tissues. Furthermore, there are decreased markers for CMA and mitochondrial quality control in the muscle whereas they are unchanged in the heart. The fuel preference and metabolism are differentially altered in these two tissues during aging, with skeletal muscle from aged mice showing a metabolomic signature suggestive of insulin resistance and fatty acid fuel inflexibility whereas the heart exhibited decreased fatty acid β-oxidation. These differential effects in muscle and heart metabolism during aging suggest that different types of metabolic derangements may occur in muscle vs. heart, and thus may require different therapeutic approaches to optimize the function of these two tissues during aging and aging-associated diseases.

Age-related changes in cardiac homeostasis can be observed at the cellular, extracellular, and tissue levels. Progressive cardiomyocyte hypertrophy, inflammation, and the gradual development of cardiac fibrosis are hallmarks of cardiac aging. In the absence of a secondary insult such as hypertension, these changes are subtle and result in slight to moderate impaired myocardial function, particularly diastolic function. While collagen deposition and cross-linking increase during aging, extracellular matrix (ECM) degradation capacity also increases due to increased expression of matrix metalloproteinases (MMPs).

Of the MMPs elevated with cardiac aging, a number of studies have assessed MMP-9 in cardiac aging. There is strong evidence that MMP-9 is a major mediator for increased stiffness in the aging heart. In addition to proteolytic activity on ECM components, MMPs oversee cell signaling during the aging process by modulating cytokine, chemokine, growth factor, hormone, and angiogenic factor expression and activity. In association with elevated MMP-9, macrophage numbers increase in an age-dependent manner to regulate the ECM and angiogenic responses. Understanding the complexity of the molecular interactions between MMPs and the ECM in the context of aging may provide novel diagnostic indicators for the early detection of age-related fibrosis and cardiac dysfunction. One possible direction is to better understand how MMP activities could be modified to prevent or slow the development of excessive cardiomyocyte hypertrophy and ECM deposition. Aging is a resetting of baseline values to set a new homeostasis, and attempts to delay or prevent this shift may improve the cardiac aging phenotype.

Researchers have shown that immune cells in older tissues lack coordination and exhibit much more variability in gene expression compared with their younger counterparts. We've all witnessed the progressive decline of function that comes with ageing, but what exactly causes this decline - and why does it happen at different rates for different parts of the body? To find answers, scientists need to unpick all of the mechanisms of ageing at the molecular level, for every tissue. This study focused on immune tissue: specifically, CD4+ T cells.

The immune system is like a symphony orchestra, with many different types and subtypes of cells working together to fight infections. But as the immune system ages, its response to infection weakens for reasons that are not yet clear. One long-standing debate amongst scientists concerns two central hypotheses: either the functional degradation is caused by a loss of cellular performance, or it is down to a loss of coordination among cells. To resolve the debate, scientists have studied many different cell types, analysing 'average' gene expression profiles. This study employed high-resolution single-cell sequencing technology to create new insights into how cell-to-cell variability is linked with ageing. The researchers sequenced the RNA of naïve and memory CD4+ T cells in young and old mice, in both stimulated and unstimulated states. Their findings clearly showed that loss of coordination is a key component of the impaired immune performance caused by T cell ageing.

"Imagine the immune system as a 'cell army', ready to protect the body from infection. Our research revealed that this army is well coordinated in young animals, with all the cells working together and operating like a Greek phalanx to block the infection. This tight coordination makes the immune system stronger, and allows it to fight infection more effectively. We show that as the animal gets older, cell coordination breaks down. Although individual cells might still be strong, the lack of coordination between them makes their collective effectiveness lower." Previous studies have shown that in young animals, immunological activation results in tightly regulated gene expression. This study further reveals that activation results in a decrease in cell-to-cell variability. Ageing increased the heterogeneity of gene expression in populations of two mice species, as well as in different types of immune cells. This suggests that increased cell-to-cell transcriptional variability may be a hallmark of ageing across most mammalian tissues.