Fight Aging! Newsletter, February 25th 2019

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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  • Harmful Signals Secreted by Senescent Cells Depend on the Presence of Senescence-Associated Heterochromatin Foci
  • John W. Campbell, Editor of Astounding Science Fiction, Described Actuarial Escape Velocity in 1949
  • A Ribosomal DNA Epigenetic Clock is an Unexpectedly Accurate Measure of Age
  • Restoration of Lapsed Mitophagy as a Potential Treatment for Alzheimer's Disease
  • Mitochondrial Antioxidants as a Contributing Cause of Naked Mole-Rat Longevity
  • White Blood Cells Degrade Capillary Blood Flow to Contribute to Age-Related Neurodegeneration
  • Interviewing Kelsey Moody of Ichor Therapeutics at the Longevity Leaders Conference
  • A Study of Cell Size in the Context of Cellular Senescence
  • A Small Molecule NNMT Inhibitor Puts Aged Stem Cells Back to Work to Improve Muscle Regeneration in Old Mice
  • Calcification of Arteries is an Independent Cardiovascular Risk, Distinct from Atherosclerosis and Inflammation
  • An Effort to Compensate for the Age-Related Dysfunction of GABA Neurotransmission
  • Transplantation of Young Bone Marrow Improves Brain Function in Old Mice
  • Inflammaging and Degenerative Joint Disease
  • Gene Therapy to Disable Lamin A as a Potential Treatment for Progeria
  • Towards Universal Cell Lines and Tissues Grown from Induced Pluripotent Stem Cells

Harmful Signals Secreted by Senescent Cells Depend on the Presence of Senescence-Associated Heterochromatin Foci

Now that senescent cells are widely acknowledged as a cause of aging and age-related disease, and now that a large industry is forming to find ways to destroy or otherwise render harmless these cells, a great deal more investigative work into the biochemistry of senescence is taking place than was the case in earlier years. While destruction is very straightforward, and certainly easier to engineer at the present time, a sizable faction of scientists are interested in finding ways to turn off the harmful signals secreted by senescent cells. It is this signaling, the senescence-associated secretory phenotype (SASP), that causes all of the damage: chronic inflammation; destructive remodeling of the surrounding tissue structure; encouraging nearby cells to also become senescent; and so forth.

Because the SASP is complicated and poorly mapped, and no doubt depends on the operation of scores of interacting mechanisms inside a cell, and few of those mechanisms are particularly well mapped in this context, it seems to me that investigating ways to modulate the SASP is more of an academic exercise than a road to therapies at the present time. It cannot possibly compare in efficiency to destroying senescent cells. The only reason to avoid destroying these cells would be the discovery of essential senescent populations, such as neurons in the brain that are both senescent and carrying out vital functions, perhaps. So far that hasn't been the case: old mice do just fine when given senolytic therapies to destroy senescent cells throughout the body, including the brain.

Nonetheless, we might ask whether or not there are master regulators of the SASP yet to be discovered. If so, their existence might make SASP suppression a more viable proposition in the future. The open access research results below may represent a step in that direction. The researchers have found what looks like a fairly important point of control for the SASP, or at least a point of dependency, and that suggests the possibility of a master regulator, even if the exact mechanism examined here turns out to be infeasible as the basis for a point of intervention (which seems quite likely to be the case at first glance).

Study sheds light on damage linked to ageing

Some of the damaging cell effects linked to ageing could be prevented by manipulating tiny parts of cells, a study shows. Scientists have shed light on how the harm caused by senescence - a vital cell process that plays a key role in diseases of ageing - could be controlled or even stopped. Researchers say the findings could have relevance for age-related diseases, although they caution that further research is needed.

During senescence, cells stop dividing. This can be beneficial in assisting wound-healing and preventing excessive growth. Some aspects of senescence are also harmful and can lead to tissue damage and the deterioration of cell health as seen in diseases of older age. Researchers focused on a chain of harmful processes triggered by senescence, known as the senescence-associated secretory phenotype (SASP). The SASP is a cascade of chemical signals that can promote damage to cells through inflammation. The researchers showed that manipulating a cell's nuclear pores - gateways through which molecules enter the heart of the cell - prevented triggering of the SASP. Findings also show that DNA had to be reorganised in space within in the cell nucleus in order for the SASP to be triggered.

Nuclear pore density controls heterochromatin reorganization during senescence

Three-dimensional (3D) genome organization is governed by a combination of polymer biophysics and biochemical interactions, including local chromatin compaction, long-range chromatin interactions, and interactions with nuclear structures. One such structure is the nuclear lamina (NL), which coats the inner nuclear membrane and is composed of lamins and membrane-associated proteins, such as Lamin B receptor (LBR). Large blocks of heterochromatin are associated with the nuclear periphery, and mapping genome interactions with laminB1 identifies more than 1000 lamina-associated domains (LADs).

One situation in which there is a dramatic reorganization of heterochromatin is in oncogene-induced senescence (OIS) - a cell cycle arrest program triggered by oncogenic signaling. OIS cells undergo striking chromatin reorganization with loss of heterochromatin and constitutive LADs from the nuclear periphery and the appearance of internal senescence-associated heterochromatin foci (SAHFs). SAHFs are not observed in nontransformed replicating cells.

The nuclear envelope is perforated by nuclear pores that control transport between the cytoplasm and nucleus. The nuclear pore complex (NPC) is a large transmembrane complex consisting of ∼30 proteins called nucleoporin. The nuclear area underneath nuclear pores is devoid of heterochromatin. The nucleoporin TPR has been shown to be responsible for heterochromatin exclusion zones at the NPC.

The composition and density of the NPC change during differentiation and tumorigenesis. We therefore hypothesized that the NPC could contribute to global chromatin organization and that, specifically, heterochromatin organization could result from a balance of forces attracting heterochromatin to the NL and forces repelling it away from the NPC. In support of this hypothesis, we show here that nuclear pore density increases during OIS and that this increase is necessary for heterochromatin reorganization into SAHFs. We identified TPR as a key player in this reorganization. Furthermore, we demonstrated the functional consequences of heterochromatin reorganization in OIS for the programmed activation of inflammatory cytokine gene expression: the senescence-associated secretory phenotype (SASP).

John W. Campbell, Editor of Astounding Science Fiction, Described Actuarial Escape Velocity in 1949

Some of the voices of the past can appear entirely contemporary, because they saw further and with greater clarity than most of their peers. John W. Campbell, editor of Astounding Science-Fiction Magazine, died of heart disease at age 61 in 1971. In 1949 he wrote an editorial on the future of medicine, aging, and longevity that wouldn't seem out of place today. He anticipated what we presently call actuarial escape velocity, or longevity escape velocity, the idea that gains in life span through progress in medical technology allow greater time to benefit from further gains - and eventually, we are repaired more rapidly than we are damaged, escaping from aging. These commentaries of past years, printed on paper, often vanish into the void. Fortunately this one remains.

As was the case for Timothy Leary in the 1970s, Campbell in 1949 overestimated what could be achieved with the technology of his near future. They were not the first to do so. Thus those of us who have advocated and raised funds for the rejuvenation biotechnology of today must have an argument as to why this decade is different, why we are not doomed to a certainty of aging to death just like Leary and Campbell. That argument must be detailed, robust, and heavily scientific.

That argument exists! Look no further than the SENS rejuvenation research programs and the extensive supporting evidence for the effectiveness of working to repair the root cause molecular damage of aging. This approach is different from the hypothetical approaches to intervene in aging that were proposed in the past - though Campbell is closer to it than Leary. The SENS thesis on aging predicted that senolytics to clear senescent cells from old tissues would be effective as a means of rejuvenation, and now we are finding that this is in fact the case. Senolytics robustly turn back all manner of measures of aging and age-related disease in animal studies. Implementing the rest of the SENS agenda, to repair or work around the molecular damage at the root of aging, is the way to demonstrate that, yes, it is different this time around.

Oh King, Live Forever!... - Astounding Science-Fiction Magazine, Vol. 43, No. 2, April, 1949

At some point in the history of the world and the history of medical science, a point will be reached such that a child born at that time can, if he chooses - and has reasonable luck so far as mechanical damage goes - live practically forever. This point in time will be some forty or more years before the perfection of the full requirements for continuous life - and this point may already have passed, without our knowing it.

For it is inherent in the nature of things that the critical birth-period can not be known until after the event - until after the perfection of the final techniques. Modern medical techniques have been developed to a high point - and on an exponential curve of progress, as is normal in an advancing science - with a view to keeping children and young adults happy, healthy and reasonably sane. The rise in the average-age-at-death statistics has been largely influenced by the diminution of infant and young-adult mortality; medical science has been devoting the greater measure of its efforts to that end of the problem.

Now, with an increasingly older population group, with increasing masses of people in the older age brackets as their biggest problem, systemic failure type medical problems, rather than acute infectious problems will predominate. Heart disease takes the place of diphtheria; cancer replaces tuberculosis. Childbirth fever is vanquished - the problem is hardening of the arteries. Pediatrics is a well-advanced science; gerontology, its opposite number, is practically an unexplored field.

The first achievements of an advancing study of "old age and why is it" will naturally be concentrated on the typical conditions that kill the aged - systemic failure troubles such as heart and artery breakdowns. Of course, the only real cure for the systemic failures of the aged is the very simple and obvious one - youth. Not chronological youth, but metabolic youth. Research must be done on that problem, and is being done. The efforts being made at any time will, of course, be basically palliative - treatments that are primarily symptomatic. The obvious symptom of trouble is heart disease; the cause is old age. The medical profession assures itself that it isn't out to find the secret of eternal youth - simply to cure heart disease. But if it succeeds in cleaning up all the symptoms, one by one, the sum total of the results must, necessarily, be metabolic youth.

Some of the more forthright researchers are headed directly toward the more all-inclusive goal of extended maturity - i.e., extended youth. The two groups of researches will, inevitably, meet on a middle ground of success, sooner or later. For the present and near-future, say twenty years hence, we can expect some very real extensions in active life span, before the onset of the symptoms which, collectively, are termed "old age", and, simultaneously, a successful attack on the more outstanding problems of old age. The combined effect may be to extend the useful period of life as much as thirty years. Certainly not a figure to be confused with "eternal youth" - but pleasant none the less.

During the next succeeding years, incidentally, progress may well be at a faster rate. If the maturity extension techniques are applied to the research workers themselves - naturally! - the experience and ability gained in the previous years of work will be available to aid in further advances. Instead of spending thirty-five years learning how, and then twenty-five years doing research, a man with an added thirty years of life would be a far more efficient unit of civilization; a non-producer for thirty-five years, he could be a producer for fifty-five!

And the great problem really can't be very extreme: the human metabolism is already so nearly perfectly balanced that it takes many decades of very slow accumulation of imbalances to bring on old age. So small a factor of failure certainly should be correctable - and a small advance should mean a large improvement. With the accumulated knowledge and techniques of the previous research, the second twenty years of work might well see a further extension of maturity by another couple of decades.

The first advance of thirty years would be no "eternal youth" treatment. But - science tends to advance exponentially. That thirty-year reprieve might give just the time needed for research to extend your life another forty years. And that forty years might ... We don't know, nor can we guess now, when in time that critical point will arrive - or has arrived. But somewhere in history there must come a point such that a child born then will be just passing maturity when the life-extension techniques will reach the necessary point. They will grant him a series of little extensions - each just sufficient to reach the next - until the final result is achieved. I wonder if that point has been passed? And my own guess is - it has.

A Ribosomal DNA Epigenetic Clock is an Unexpectedly Accurate Measure of Age

Epigenetic clocks are a weighted combination of DNA methylation at specific sites on the genome. Modern processing power allowed the association between these algorithms and aging to be reverse engineered, but it remains an open question as to what exactly is being measured. What underlying processes of aging are reflected by these characteristic epigenetic changes? All of them? Some of them? Some more than others? No-one knows in certainty, though the specific genes and proteins involved offer some suggestions. Until researchers have a better idea on that front, it is hard to use these clocks in the way we all want them to be used: to greatly speed up development of rejuvenation therapies. If it was possible to take a measure, apply a therapy, and then within days or a month at most take a second measure, and on that basis declare whether or not a particular approach works, then the assessment of potential methods of rejuvenation could proceed quite rapidly indeed.

Epigenetic clocks are evolving as researchers explore this association between DNA methylation and aging. The most interesting aspect of the new clock noted below is that only a tiny portion of the genome is involved. Even though it is apparently very similar in diverse species, to me this sounds like there is an even greater risk that the clock only measures a small slice of the many important processes of aging, and thus won't be all that helpful for the development of rejuvenation therapies. In a world without the ability to intervene in specific processes of aging, all of those processes in any given individual tend to be aligned with one another. But if just one of those processes is reversed - such as by clearance of senescent cells - then assessment will become a problem if epigenetic clocks behave unpredictably in this sort of scenario.

In practice, what is going to happen is that measures of aging and rejuvenation will be developed in parallel to the development of rejuvenation therapies. Perhaps epigenetic clocks will be increasingly calibrated to report on the outcome of clearance of senescent cells, for example. This seems likely, as the industry will want something more than just counts of cells and reversal of symptoms for one specific age-related disease to show that they are affecting the course of aging in a profound way. But that tailored epigenetic clock may well turn out to be useless for, say, assessing the effects of cross-link breaking on the progression of aging. Nothing is simple in biochemistry. We might hope for a universal assessment of age to turn up sometime soon, to speed up research and development, but it may well be the case that the only practical way to build such a measure is to first make significant progress in all of the areas of the full SENS program of rejuvenation therapies.

Uncovering a "smoking gun" of biological aging

Researchers looked at ribosomal DNA (rDNA), the most active segment of the genome and one which has also been mechanistically linked to aging in a number of previous studies. They hypothesized that the rDNA is a "smoking gun" in the genomic control of aging and might harbor a previously unrecognized clock. To explore this concept, they examined epigenetic chemical alterations (also known as DNA methylation) in CpG sites, where a cytosine nucleotide is followed by a guanine nucleotide. The study homed in on the rDNA, a small (13 kilobases) but essential and highly active segment of the genome, as a novel marker of age.

Analysis of genome-wide data sets from mice, dogs, and humans indicated that the researchers' hypothesis had merit: numerous CpGs in the rDNA exhibited signs of increased methylation - a result of aging. To further test the clock, they studied data from 14-week-old mice that responded to calorie restriction, a known intervention that promotes longevity. The mice that were placed on a calorie-restricted regimen showed significant reductions in rDNA methylation at CpG sites compared with mice that did not have their caloric intake restricted. Moreover, calorie-restricted mice showed rDNA age that was younger than their chronological age.

The researchers were surprised that assessing methylation in a small segment of the mammalian genome yielded clocks as accurate as clocks built from hundreds of thousands of sites along the genome. They noted that their novel approach could prove faster and more cost effective at determining biological and chronological age than current methods of surveying the dispersed sites in the genome. The findings underscore the fundamental role of rDNA in aging and highlight its potential to serve as a widely applicable predictor of individual age that can be calibrated for all mammalian species.

Ribosomal DNA harbors an evolutionarily conserved clock of biological aging

The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, Drosophila, and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity.

Here, we introduce an age clock built exclusively with CpG methylation within the rDNA. The ribosomal clock is sufficient to accurately estimate individual age within species, is responsive to genetic and environmental interventions that modulate life-span, and operates across species as distant as humans, mice, and dogs. Further analyses revealed a significant excess of age-associated hypermethylation in the rDNA relative to other segments of the genome, and which forms the basis of the rDNA clock. Our observations identified an evolutionarily conserved marker of aging that is easily ascertained, grounded on nucleolar biology, and could serve as a universal marker to gauge individual age and response to interventions in humans as well as laboratory and wild organisms across a wide diversity of species.

Restoration of Lapsed Mitophagy as a Potential Treatment for Alzheimer's Disease

Many research groups have published evidence to suggest that age-related mitochondrial dysfunction is an important aspect of neurodegenerative conditions such as Alzheimer's disease. The brain is an energy-hungry organ and mitochondria are the power plants of the cell, responsible for producing the chemical energy store molecules that power cellular activity. It is well known that mitochondrial function declines with age; mitochondria in old tissues are structurally different, and less effective at their jobs.

The research results here suggest that this mitochondrial decline has a lot to do with the fact that the cellular housekeeping processes of autophagy falter with age, and in particular mitophagy, the autophagic recycling of damaged or dysfunctional mitochondria. The degree of benefit seen from boosted mitophagy indicates that perhaps it is higher rather than lower in the hierarchy of mechanisms. That said, there is good evidence from other studies for lapsed mitophagy to be a consequence of deeper changes in mitochondrial dynamics that make it harder for the autophagic processes to operate. The question of the best place to intervene is probably one best settled by trying the various potential approaches in order to see how well they work.

A point worth noting, as for all Alzheimer's research, is that the animal models of this condition are highly artificial. Old mice do not normally undergoing anything even remotely akin to the processes underlying Alzheimer's disease, and thus there is always the question of whether or not the results in a mouse model have anything to do with the way in which the condition proceeds in humans. One can be reasonable confident that mitochondrial dysfunction is similar between mammalian species, based on the past few decades of research, but it is the linkage of that dysfunction to either Alzheimer's or the faux-Alzheimer's of the model that is the thorny point. I do think it reasonable to believe that improved autophagy (in general) or mitophagy (in specific) will produce some degree of benefits across the board in human cellular biochemistry - but will the benefits for Alzheimer's patients be of the same order as those observed in mice?

'Lack of Cleaning' in Brain Cells is Central to Alzheimer's Disease

Researchers have come closer to a new way of attacking Alzheimer's disease. They target the efforts towards the cleaning process in the brain cells called mitophagy. "When the cleaning system does not work properly, there will be an accumulation of defective mitochondria in the brain cells. And this may be really dangerous. At any rate, the poor cleaning system is markedly present in cells from both humans and animals with Alzheimer's. And when we improve the cleaning in live animals, their Alzheimer's symptoms almost disappear."

The researchers have looked more closely at mitophagy in brain cells from deceased Alzheimer's patients, in Alzheimer's-induced stem cells and in live mice and roundworms with Alzheimer's. In addition, they have also tested active substances targeted at mitophagy in the animal models. The mitochondria lie inside the cell and can be seen as the cell's energy factories. Mitophagy breaks down defective mitochondria and reuses the proteins that they consist of. It is known from previous research that dysfunctional mitophagy is associated with poor function and survival of nerve cells, but so far, the connection with Alzheimer's is unclear.

In both Alzheimer's and other states of dementia, there is an accumulation of the proteins tau and beta amyloid in the brain, leading to cell death. In the new animal models, the researchers show that when boosting the mitophagy, such accumulation will slow down. The researchers believe that altogether their findings indicate that mitophagy is a potential target for the treatment of Alzheimer's, which should be further investigated. They therefore plan to start clinical trials in humans in the near future.

Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease

Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models.

In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1, PDR-1, or DCT-1 dependent pathways. Mitophagy diminishes insoluble Aβ1-42 and Aβ1-40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.

Mitochondrial Antioxidants as a Contributing Cause of Naked Mole-Rat Longevity

Naked mole-rats exhibit exceptional longevity in comparison to other rodent species. They can live nine times longer than similarly sized mice, for example. There are no doubt a sizable number of distinct mechanisms that contribute to this difference in species life span, and the existence of mammals with widely divergent life spans acts as a natural laboratory for researchers interested in better understanding aging. If one species lives a much longer life than another, then using their differences in order to identify the more important aspects of cellular metabolism in the matter of aging may well be a faster approach than other strategies that aim to reverse engineer the workings of aging. Thus research groups have been energetically investigating the biochemistry of naked mole-rats for many years now.

Naked mole-rats are exceptionally resistant to cancer, to the point at which for all of the populations maintained across the years in laboratories and zoos, only a few cases of cancer have ever been reported. Of late the ability of naked mole-rats to suppress cancerous mutations and cancerous cells has become one of the primary areas of study when it comes to their metabolic peculiarities. Avoiding death by cancer probably isn't one of the most important contributions to naked mole-rat longevity, however.

Instead, it seems likely that at least some of the major determinants of longevity relate to mitochondrial function and cellular resistance to oxidative damage. The horde of mitochondria in every cell act as power plants, but also as a source of oxidative molecules. These are generated as a byproduct of the energetic chemical reactions needed to package up the adenosine triphosphate (ATP) used as fuel for cellular processes. The presence of too many oxidative molecules are harmful to cells, and mitochondria themselves can be damaged by oxidative molecules in ways that contribute to aging. The situation is far from simple, however: oxidative molecules are used as signals for cellular maintenance, and thus small or brief increases are in fact beneficial. Further, antioxidant processes in mitochondria act to clean up much of the exhaust of new oxidative molecules. This is a complex, dynamic system of oxidants and reactions to oxidants that does not lend itself to easy predictions of outcomes.

The membrane pacemaker hypothesis suggests that the important factor in all of this, when considering differences between species, is the composition of cell membranes, particularly those of mitochondria. Different cell membrane lipids are more or less vulnerable to oxidative reactions and consequent functional damage. Species like naked mole-rats, with very high levels of all of the markers of oxidative stress, yet few to no apparent consequences, are perhaps a good argument for the membrane pacemaker way of looking at things. Equally, the research here makes a different argument - that this is all about the degree to which mitochondria can direct their own antioxidant processes to consume oxidizing molecules, and naked mole-rats are much better at this than mice. It is known that raising levels of mitochondrial antioxidants, either via gene therapy or by delivering artificial antioxidants that localize to mitochondria, appears to slow aging in a number of different species. The question, as always, is the size of any specific contribution to the overall outcome.

The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses

Naked mole-rats (NMRs; Heterocephalus glaber, Rodentia) are mouse-sized eusocial mammals native to Eastern Africa that live in large subterranean colonies. Individuals of this species can live for longer than 30 years in laboratory conditions, and also exhibit a remarkably long health span; typical signs of senescence seen in old rodent are mostly absent in NMRs. Conversely, the common mouse (Mus musculus, Rodentia) lives less than 4 years and is highly susceptible to aging-related diseases and physiological decline. As a result, comparisons between these two species are considered to be a "gold standard" in mammalian studies of aging.

According to the oxidative stress theory of aging, senescence is caused by the gradual accumulation of oxidative damage to cells, inflicted by reactive oxygen species (ROS) of mitochondrial origin. However, previous comparative studies of NMR biology mostly provided evidence that contradicted this theory. For example, comparisons of isolated heart mitochondria found no difference in the rate of H2O2 efflux (i.e., the proportion of H2O2 not consumed by the mitochondrion before detection) between NMRs and mice. In addition, extensive oxidative damage and limited antioxidant capacity have been reported in the cytosol of NMR hepatocytes. Taken together, these findings led to the conclusion that the longevity of NMRs occurs independently of enhanced protection against oxidative damage, and this conclusion has been used repeatedly to refute the oxidative stress theory of aging.

More recently, however, the mitochondrial oxidative stress hypothesis of aging has gained empirical support; however, this hypothesis remains controversial, and has not yet been investigated in NMRs. This refined hypothesis stems from the fact that mitochondrial ROS are mostly released inside the mitochondrion (i.e., within the mitochondrial matrix), thereby directly exposing mitochondrial biomolecules to oxidative damage. According to the mitochondrial stress hypothesis, cellular senescence is primarily driven by loss of mitochondrial function with age. A central step toward testing this hypothesis would be to measure the balance between internal production and internal consumption of ROS within mitochondria themselves.

We have recently shown that traditional methodologies for detecting the rate of H2O2 formation from isolated mitochondria underestimate ROS generation because of the remarkable endogenous capacity of matrix antioxidants to consume H2O2. For example, this underestimation can reach 80% or more in rat skeletal muscle with certain respiratory substrates. Moreover, mitochondria can consume far more H2O2 than they generate; therefore, this capacity of mitochondria to consume H2O2 putatively represents a novel and widely underappreciated test of the mitochondrial oxidative stress theory of aging in of itself. We hypothesized that differences in the capacity of mitochondria to eliminate H2O2 might solve the apparent NMR oxidative stress/longevity-conundrum.

To test our hypothesis, we took advantage of antioxidant inhibition methods that we developed previously to measure H2O2 formation rates without the confounding influence of internal consumption. We also compared mitochondrial H2O2 clearance (i.e., maximal consumption) rates between these two species in functional isolated mitochondria. Our results support the mitochondrial oxidative stress hypothesis of aging via a mechanism that has not been previously demonstrated: NMRs and mice do not differ in their rate of H2O2 formation, but rather in the markedly greater capacity of NMR mitochondria to consume H2O2.

White Blood Cells Degrade Capillary Blood Flow to Contribute to Age-Related Neurodegeneration

Researchers here outline a new discovery regarding the origin of reduced blood flow in the aging brain; white blood cells are clogging up capillaries. It is well known that the supply of blood is reduced in tissues with age; this is studied in muscles and the brain, among other tissue types. Some researchers blame a reduction in capillary density in later life, others consider reduced capacity of the heart to pump blood uphill to the brain. A lesser flow of blood in any specific tissue will affect its function, especially in energy-hungry tissues such as the brain, as the supply of oxygen and nutrients is reduced.

In the case of the results reported here, I have to wonder whether this might tie in some way to the observed reduction in capillary density with age; does blockage by white blood cells result in significant capillary atrophy at the smallest scale of blood vessels? There are certainly other mechanisms by which that outcome could occur, and this may not be an important contribution even it does produce atrophy to some degree.

The existence of cerebral blood flow reduction in Alzheimer's patients has been known for decades, but the exact correlation to impaired cognitive function is less understood. "People probably adapt to the decreased blood flow, so that they don't feel dizzy all of the time, but there's clear evidence that it impacts cognitive function." A new study offers an explanation for this dramatic blood flow decrease: white blood cells stuck to the inside of capillaries, the smallest blood vessels in the brain. And while only a small percentage of capillaries experience this blockage, each stalled vessel leads to decreased blood flow in multiple downstream vessels, magnifying the impact on overall brain blood flow.

The work began with a study in which researchers were attempting to put clots into the vasculatures of Alzheimer's mouse brains to see their effect. "It turns out that the blockages we were trying to induce were already in there. It sort of turned the research around - this is a phenomenon that was already happening." The researchers determined that only about 2 percent of brain capillaries had "stalls" (blockages), but the cumulative effect of that small number of stalls was an approximately 20 percent overall decrease in brain blood flow, due to the slowing of downstream vessels by the capillaries that were stalled.

Recent studies suggest that brain blood flow deficits are one of the earliest detectable symptoms of dementia. To test the effect of the stalls on performance of memory tasks in Alzheimer's mice, they were given an antibody that interfered with the adhesion of white blood cells to capillary walls, which caused the stalled capillaries to start flowing again and thus increased overall brain blood flow. Memory function was improved within a few hours, even in aged mice with more advanced stages of Alzheimer's disease.

Interviewing Kelsey Moody of Ichor Therapeutics at the Longevity Leaders Conference

Ichor Therapeutics, led by Kelsey Moody, was one of the first companies to emerge from the core SENS Research Foundation community. The company has grown over the years and is now at the head of a collection of spin-out startups focused on a variety of approaches to aging, such as senolytic therapies to destroy senescent cells (Antoxerene), and clearance of a form of metabolic waste that contributes to macular degeneration (LysoClear). The influx of funding in this field that has taken place over the past couple of years is now powering Ichor Therapeutics forward towards the clinic.

Ichor and its portfolio companies have been very busy over the last year, so I thought it was time that we caught up on progress. Can you tell us how things are going for the Ichor group?

Ichor really had a good year in 2018. We raised over 16 million across our portfolio, and that's allowed us to scale up all aspects of our operations. We're at over 50 employees now, mostly bench scientists and research technicians, and we're really delivering on our goal of being a vertically integrated biopharmaceutical company. What that means is we want to be able to take any idea, regardless of what it is, such as a type of compound or therapeutic indication, and rapidly turn it from the discovery stage, through the pipeline, into the first demand studies. The additional capital that we've raised and the infrastructure that we're putting online are really allowing us to put that all together to support the field of longevity.

Juvenescence and you made a collaborative project called FoxBio. How's that going?

Unfortunately, I can't say a whole lot about the progress on FoxBio, except to say that I'm very, very bullish on it and very excited about the prospects and implications. We are very excited to partner with Juvenescence due to the depth of experience that they bring to the drug discovery process and the insights that they have about creating not just strong drug development and discovery programs but also company structures and platforms that allow entities to raise the large amount of capital that is necessary for clinical trials, as it's just a huge value add to the core portfolio. We found them to be great to work with, and we're really excited to expand the scope of that relationship over time.

What's the news on Lysoclear, the therapy for adult age-related adult blindness?

Again, I can't talk a whole lot about the specifics, but we did close a financing round in December of 2018 to move from our proof-of-concept lead drug candidate to a clinical candidate that would be suitable for first-demand studies. We're in the process of putting together our plan to reach IND (investigational new drug) status. IND in the US system is the point at which you're able to go into human trials for the first time. That requires all kinds of backend support, from manufacturing your product under good manufacturing processes (GMP) to toxicology studies and so forth. We were very fortunate last year to recruit a chief medical officer who has a lot of experience in drug development and discovery. He's got about 12 drugs and medical devices under his belt and about 185 clinical trials in the macular degeneration space. We're very enthusiastic to have someone with that depth of expertise, really taking the reins on our clinical planning and making sure that when we're ready with our candidate to pull the trigger, we're able to navigate clinical and regulatory issues that might arise.

An area that has been problematic in the past has been taking the research from a basic stage to a translational point where it can then go to market. Has that improved in the last few years?

Yeah, I think so. I think there's a lot of academic labs in particular now that have an eye for spinning out companies, particularly with new groups emerging in the area. Juvenescence, of course, is licensing different types of technology and having a partnership with the Buck Institute, for example, and Life Biosciences, a new player in the space, is bringing in substantial amounts of capital to assist academic labs with translating programs. What's really exciting about all of this is when you bring these sophisticated drug developers into this space, you're adding a certain level of robustness to the discovery process that might not necessarily exist in a traditional academic setting. It really allows you to combine the best of both worlds.

How did you develop your career from someone who was a high school and college athlete to where you are now?

Well, like a lot of people that are really trying to start companies and do things in this space, I started by reading a book, Aubrey de Grey's book, in fact, Ending Aging, which I think was published a little over a decade now. I told myself that I'm going to switch to biochemistry as a major, and I'm going to pursue this line of work until I am certain that Aubrey is wrong. Despite my very best efforts, I have not been able to get to any sort of definitive conclusion on that. He still might be, and many have tried to prove him wrong, but the trend is in his favor. That, of course, took me to work with Aubrey at SENS Research Foundation and various startups in Silicon Valley and then eventually become a medical student where I currently am.

One of the really interesting things that I think is underappreciated about the SENS paradigm, and is a central component to how we're structuring our companies, is really this damage repair approach. A lot of people like the SENS damage repair approach that Aubrey put forth because it's something that we can understand and the whole argument of sidestepping the ignorance of metabolism, and so forth. What's underappreciated by most people that do drug development, that I think is worth highlighting here, is that the sorts of therapies that would emerge from this line of thinking are therapies that are going to be used intermittently, and that is hugely beneficial from a development perspective. That creates a huge opportunity for drug developers to bring in whole new classes of drugs that are actually able to mitigate many of these diseases of aging in a way that's rather unprecedented and very much defies the chronic-administration sort of model that we're familiar with in this space.

A Study of Cell Size in the Context of Cellular Senescence

Senescent cells are a major problem in our bodies, in that their growing presence over the years is an important cause of degenerative aging. Unfortunately, the research community can't just prevent cells from ever becoming senescent, even were the capacity to do that in hand today, because transient senescence serves many useful, even necessary purposes in our biochemistry. It is only the lingering senescent cells that are the problem. Periodically removing these unwanted, harmful cells is a very viable way forward, however, and a new biotechnology industry is springing up to do just that.

One very interesting point about senescent cells is that they are notably larger than normal cells. One research group has produced a way of counting senescent immune cells from a blood sample based on sorting by size. Another measured the sizes of cells in old hearts, before and after clearing out senescent cells with a senolytic treatment, showing that the senescent cells were larger. I have to think that there is something useful, potentially even important, that can be done with this feature of senescent cells - the clever implementation just hasn't arrived yet.

In multicellular organisms, cell size ranges over several orders of magnitude. This is most extreme in gametes and polyploid cells but is also seen in diploid somatic cells and unicellular organisms. While cell size varies greatly between cell types, size is narrowly constrained for a given cell type and growth condition, suggesting that a specific size is important for cell function. Indeed, changes in cell size are often observed in pathological conditions such as cancer, with tumor cells frequently being smaller and heterogeneous in size. Cellular senescence in human cell lines and budding yeast cells is also associated with a dramatic alteration in size: senescing cells become exceedingly large. Cell size control has been studied extensively in a number of different model organisms, but why cell size may need to be tightly regulated is not known.

Several considerations argue that altering cell size is likely to have a significant impact on cell physiology. Changes in cell size affect intracellular distances, surface to volume ratio and DNA:cytoplasm ratio. It appears that cells adapt to changes in cell size, at least to a certain extent. During the early embryonic divisions in C. elegans, as cell size decreases rapidly, spindle size shrinks accordingly. Other cellular structures such as mitotic chromosomes, the nucleus and mitochondria have also been observed to scale with size in various organisms. Similarly, gene expression scales with cell size in human cell lines as well as in yeast.

However, not all cellular pathways can adapt to changes in cell size. For example, signaling through the spindle assembly checkpoint, a surveillance mechanism that ensures that cells enter anaphase only after all chromosomes have attached to the mitotic spindle, is less efficient in large cells in C. elegans embryos. In human cell lines, maximal mitochondrial activity is only achieved at an optimal cell size. Finally, large cell size has been shown to impair cell proliferation in budding yeast and human cell lines.

Here we identify the molecular basis of the defects observed in cells that have grown too big. We show that in large yeast and human cells, RNA and protein biosynthesis does not scale in accordance with cell volume, effectively leading to dilution of the cytoplasm. This lack of scaling is due to DNA becoming rate-limiting. We further show that senescent cells, which are large, exhibit many of the phenotypes of large cells. We conclude that maintenance of a cell type-specific DNA:cytoplasm ratio is essential for many, perhaps all, cellular processes and that growth beyond this cell type-specific ratio contributes to senescence.

A Small Molecule NNMT Inhibitor Puts Aged Stem Cells Back to Work to Improve Muscle Regeneration in Old Mice

In old tissues, stem cell activity is much reduced relative to youthful activity. This is thought to be the most important contribution to loss of muscle mass and strength with age, leading to the condition known as sarcopenia. It also diminished the ability to regenerate after muscle injury. Numerous studies in the regenerative medicine community have demonstrated that while this loss of stem cell function may be a defense against cancer, reducing the activity of cells that may bear potentially dangerous molecular damage, there appears to be a fair amount of room to push the balance towards greater activity without large increases in cancer risk. In mice, anyway.

Researchers here demonstrate a novel way of increasing muscle stem cell activity, to add to a number of others that have been shown to work to some degree in animal studies. The mechanism is arguably somewhat related to work on ways to increase levels of NAD+ so as to enhance mitochondrial activity in old tissues. Here the effect size on muscle regeneration in mice is certainly large enough to be interesting. We'll no doubt see what it does in humans fairly soon, even ahead of human trials, as the self-experimentation community decides to try this out. One would hope they would go about it more carefully than is usually the case in body building circles.

Aging is accompanied by progressive declines in skeletal muscle mass and strength and impaired regenerative capacity, predisposing older adults to debilitating age-related muscle deteriorations and severe morbidity. Muscle stem cells (muSCs) that proliferate, differentiate to fusion-competent myoblasts, and facilitate muscle regeneration are increasingly dysfunctional upon aging, impairing muscle recovery after injury. While regulators of muSC activity can offer novel therapeutics to improve recovery and reduce morbidity among aged adults, there are no known muSC regenerative small molecule therapeutics.

We recently developed small molecule inhibitors of nicotinamide N-methyltransferase (NNMT), an enzyme overexpressed with aging in skeletal muscles and linked to impairment of the NAD+ salvage pathway, dysregulated sirtuin 1 activity, and increased muSC senescence. We hypothesized that NNMT inhibitor (NNMTi) treatment will rescue age-related deficits in muSC activity to promote superior regeneration post-injury in aging muscle.

24-month old mice were treated with saline (control), and low and high dose NNMTi for 1-week post-injury, or control and high dose NNMTi for 3-weeks post-injury. In vivo contractile function measurements were conducted on the injured tibialis anterior (TA) muscle and tissues collected for ex-vivo analyses, including myofiber cross-sectional area (CSA) measurements to assess muscle recovery. Results revealed that muscle stem cell proliferation and subsequent fusion were elevated in NNMTi-treated mice, supporting nearly 2-fold greater CSA and shifts in fiber size distribution to greater proportions of larger sized myofibers and fewer smaller sized fibers in NNMTi-treated mice compared to controls.

Prolonged NNMTi treatment post-injury further augmented myofiber regeneration evinced by increasingly larger fiber CSA. Importantly, improved muSC activity translated not only to larger myofibers after injury but also to greater contractile function, with the peak torque of the TA increased by ∼70% in NNMTi-treated mice compared to controls. Taken together, these results provide the first clear evidence that NNMT inhibitors constitute a viable pharmacological approach to enhance aged muscle regeneration by rescuing muSC function.

Calcification of Arteries is an Independent Cardiovascular Risk, Distinct from Atherosclerosis and Inflammation

The same underlying molecular and cellular damage of aging contributes to both calcification of blood vessel walls and the development of atherosclerosis, but researchers here argue that calcification can be considered on its own, an independent risk factor for cardiovascular dysfunction and mortality in later life. The presence of senescent cells is one of the common underlying factors that accelerates the progression of both atherosclerosis and calcification of blood vessels. This is due to the inflammatory signaling produced by these cells. That signaling distorts the behavior of macrophages trying to clear up deposits of cholesterol in blood vessel walls, but also makes other cells in the wall behave as though they are osteoblasts in bone, laying down mineral deposits.

Calcification, like the creation of cross-links or degradation of elastin in the extracellular matrix, is harmful because it reduces elasticity in blood vessels. That loss of elasticity breaks the feedback mechanisms that control blood pressure, and the result is the development of hypertension. Hypertension causes structural damage throughout the body: small blood vessels rupture at an accelerated rate in the delicate tissues of the brain, kidney, and other organs, killing tiny sections of tissue. Further, hypertension accelerates the progression of atherosclerosis, and increases the chance of a fatal breakage in blood vessels weakened by atherosclerotic lesions.

In 1903, scientists described typical concentric calcifications in the medial arterial wall as a distinct phenomenon from atherosclerotic plaques. These medial arterial calcifications (MAC) have long been considered as innocent normal aging. Current treatments for cardiovascular disease target luminal thrombosis and atherosclerosis in the intimal layer. Despite widespread preventative efforts, residual cardiovascular disease burden remains high. We hypothesize that arterial calcification, especially in the medial arterial layer, contributes to this residual cardiovascular risk.

Testing this hypothesis is relevant given the high prevalence of arterial calcifications in the population. Causal investigation, independent of inflammation, dyslipidaemia, and thrombosis is difficult and the diagnosis of MAC is challenging as intimal and medial calcification often co-occur. In the human body a complex network of calcification promoters and inhibitors is precisely tuned to inhibit MAC. Inorganic pyrophosphate (PPi) is one of the most potent calcification inhibitors in humans. It binds to hydroxyapatite crystals, thereby inhibiting further growth of the calcifications. The consequences of disrupted PPi homeostasis are shown in genetic disorders. These patients suffer from accelerated aging which results in severe visual impairment, peripheral arterial disease, gastric bleeding, ischemic stroke, and cerebral white matter lesions.

How relevant can this be for patients with diabetes, chronic kidney disease, and for aging in the general population? It is clear that the residual burden and health care costs for cardiovascular disease are huge. MAC contributes to arterial stiffening which results in hypertension and heart failure, but also to pulse pressure-related damage in susceptible high flow end-organs like the kidney and the brain. Indeed increased arterial stiffness is associated with worsening of chronic kidney disease and microvascular brain damage and might therefore contribute to the development and progression of cognitive decline.

In the general population, MAC is shown to be the predominant type of calcification in leg arteries and probably also in the intracranial carotid artery. In the femoral and crural arteries of leg amputees, 71% of the arteries contained MAC whereas in only 31% calcified atherosclerotic lesions were seen. These calcifications are the strongest predictor of major cardiovascular events such as stroke and leg amputation and also linked to dementia, heart failure, and kidney failure. Probably, these ectopic calcifications have evolved as a defence mechanism against resistant infections and, in a pre-antibiotic era with a much shorter life expectancy, have aided survival and population growth. In our era, preventing and removing MAC maybe essential for healthy vascular aging, prevention of chronic cardiovascular events and multi-organ failure and might contribute to further decrease of residual cardiovascular risk.

An Effort to Compensate for the Age-Related Dysfunction of GABA Neurotransmission

There is plenty of evidence for progressive dysfunction in neurotransmission related to GABA to be important in forms of cognitive decline, particularly relating to memory. A number of approaches to treat this loss have been considered, with the one noted here the most recent of the type. Exactly why GABA-related dysfunction occurs in the brain is a matter for debate; as for so much of aging, there is no well-mapped line of cause and consequence leading from the fundamental damage that causes aging to the observed changes in cell behavior the aging brain. There are two approaches to dealing with this ignorance. The first is to repair the well-known forms of damage, and see what happens - the SENS rejuvenation biotechnology methodology. The second, far more popular, approach is to try to compensate for the late stage, downstream dysfunction in some way, without addressing the causes.

This second strategy, the far worse strategy, describes near all of the development of medicine for age-related disease over the past century, and its dominance in the research community is why little progress has been made. There is nothing harder than trying to keep a damaged machine running without repairing the damage. Nonetheless, as capacities in biotechnology grow, these attempts do become incrementally better. It is still absolutely the wrong approach to the challenge, but people continue to be lured back in by the steady improvement in outcomes. Of course, given that most prior outcomes are marginal at best, it doesn't take much for new initiatives to look better in comparison.

New therapeutic molecules show promise in reversing the memory loss linked to depression and aging. What's unique and promising about these findings, in the face of many failures in drug development for mental illness, is that the compounds are highly targeted to activate the impaired brain receptors that are causing memory loss. Researchers first identified the specific impairments to brain cell receptors in the GABA neurotransmitter system. Then they showed that these impairments likely caused mood and memory symptoms in depression and in aging.

The new small molecules were invented to bind to and activate this receptor target. The idea was that they would exert a therapeutic effect by "fixing" the impairment, resulting in an improvement in symptoms. The molecules are chemical tweaks of benzodiazepines, a class of anti-anxiety and sedative medications that also activate the GABA system, but are not highly targeted.

A single dose of these new molecules was administered in preclinical models of stress-induced memory loss. Thirty minutes later, memory performance returned to normal levels, an experiment that was reproduced more than 15 times. In another experiment involving preclinical models of aging, memory declines were rapidly reversed and performance increased to 80 per cent after administration, essentially reaching levels seen in youth or earlier stages of adulthood. This improvement lasted over two months with daily treatment.

Transplantation of Young Bone Marrow Improves Brain Function in Old Mice

The immune cells of the brain are somewhat different in character and function from those of the body. They have a greater portfolio of tasks beyond chasing down pathogens, clearing out waste, and assisting in regeneration. For example, the immune cells known as microglia are involved in the maintenance of synaptic connections between neurons. Interestingly, microglia are not produced in the bone marrow by stem cells or progenitor cells, so in the research here in which young bone marrow is transplanted into old mice, one can be fairly sure that any beneficial effects on microglia result from signaling differences on the part of the rest of the immune system.

At the surface, this seems like a case of improvement in function resulting from a reduction in chronic inflammation. That is perhaps reasonable to expect if the immune system becomes less damaged by age, is given more competent cells capable of managing the inflammatory process. Inflammation without end is very problematic in all tissues, the brain included, and is a significant contributing factor in the many dysfunctions of aging. It disrupts the normal behavior of near all cell types. Microglia in particular are prone to behaving unhelpfully in an inflamed environment, contributing to damage rather than helping to repair it or maintain normal function.

Surgically attaching old mice to young mice so that they share a circulatory system (heterochronic parabiosis) has been reported to rejuvenate old mice and accelerate aging in young mice. Rejuvenation of the brain, heart, liver, and pancreas of old parabionts by young blood is thought to be partly due to effects on stem cell populations. In particular, improved cognitive function has been attributed to increased neurogenesis and synaptic plasticity, as well as better brain vascularization and myelination. A single blood exchange between old and young mice, which replaces the blood without organ sharing or complications associated with the parabiosis procedure, has also recently been reported to have similar effects.

Circulating levels of CCL11 and β2-microglobulin have previously been reported to increase with age in mice and humans, and shown to promote brain aging when administered to young mice. Both CCL11 and β2-microglobulin can be produced by a diverse range of cell types, and the tissues or organs responsible for their elevated levels during aging have not been defined. Thus, the role of the hematopoietic system in these effects is unclear. CCL11 and β2-microglobulin are thought to act by suppressing neurogenesis in the hippocampus. However, the role of neurogenesis in the adult brain is controversial. Thus other mechanisms may be responsible for the rejuvenated cognitive function in old mice undergoing heterochronic parabiosis or plasma transfer. Indeed, while stem cell populations in the neurogenic niche have been closely examined, it is not known whether aging-associated changes in glial cells are also reversed.

We therefore established a heterochronic bone marrow transplant (BMT) model to determine the specific influence of systemic hematopoietic aging on cognitive function, including glial cells in the hippocampus. This approach also allowed us to evaluate the long-term beneficial impact of a young hematopoietic system on the aging brain, and define the role of the hematopoietic system in aging-associated elevation of circulating levels of CCL11 and β2-microglobulin. We found that reconstitution of old mice with young, but not old, hematopoietic cells prevented cognitive decline. BMT achieved preservation of cognitive function for at least 6 months. Microglial activation was reduced, and synaptic connections were maintained. Our data also attribute the aging-associated elevation of circulating β2-microglobulin levels to non-hematopoietic cells. In contrast, the increased CCL11 appears either to be of hematopoietic origin or to be produced by non-hematopoietic cells under hematopoietic control, and our data implicate CCL11 in aging-associated microglial activation and synaptic loss.

Inflammaging and Degenerative Joint Disease

The age-related degeneration of joint cartilage is a strongly inflammatory condition, in which the accumulation of senescent cells plays an important role. Senescent cells produce potent inflammatory signaling that harms the local environment in a range of ways. Systemic inflammation is also thought to be a meaningful contribution to osteoarthritis, however. The immune system becomes dysfunctional throughout the body with age, becoming more active and inflammatory even as it becomes ever less capable of defending against pathogens and errant cells. Minimizing joint issues with aging will no doubt require dealing with both local and systematic sources of chronic inflammation.

Aging is an inevitable process in the human body that is associated with a multitude of systemic and localized changes. All these conditions have a common pathogenic mechanism characterized by the presence of a low-grade proinflammatory status. Inflammaging is systemic, chronic, and asymptomatic. It has a multifactorial aetiology including an increased number of proinflammatory cytokines, oxidative stress, immunosenescence, autophagy, or cellular DNA damage.

The incidence of osteoathritis (OA) is steadily increasing, especially among the elderly. The mechanism of articular cartilage degeneration is not necessarily the consequence of aging, but aging is considered to be a risk factor for the occurrence of OA. There is a close relationship between chondrocyte activity and local articular environment changes due to cell senescence followed by secretion of inflammatory mediators. Furthermore, systemic inflammaging can lead to cartilage destruction, pain, disability, and an impaired quality of life.

The term "chondrosenescence" refers to all age-dependent deterioration of chondrocytes as a consequence of replicative (intrinsic) and stress-induced (extrinsic) factors. There is a strong correlation between inflammaging, the presence of inflammasomes, autophagy, and chondrosenescence. Intrinsic factors in the aging process in association with extrinsic factors such as mechanical overload or different chemical stimuli act on articular cartilage. As a consequence, an inflammatory environment characterized by increased proinflammatory cytokines, chemokine, and activated proteinase occurs locally. All these lead to the aging process of chondrocytes (chondrosenescence), which favors the appearance of degenerative joint modifications.

Gene Therapy to Disable Lamin A as a Potential Treatment for Progeria

Hutchinson-Gilford progeria syndrome (HGPS), or simply progeria, is a very rare condition caused by mutation in the lamin A gene. Patients exhibit a condition that superficially resembles greatly accelerated aging. They typically die very young from forms of cardiovascular disease usually only found in much later life. Lamins are important structural proteins, and the broken form of lamin A in progeria patients, known as progerin, results in cells with misshapen nuclei and significant dysfunction. In the sense that aging is an accumulation of damage and dysfunction, progeria can thus resemble aging, but the type of damage and the details of its progression bear little resemblance to normal aging.

In the research noted here, scientists report the interesting finding that progeroid mice are actually better off with lamin A disabled than they are with progerin in circulation; this can be achieved via gene therapy. We watch work on progeria because researchers have determined that progerin is present to some degree in normal aged individuals. It remains an open question as to the degree to which this contributes to the dysfunction of aging: is it significant in comparison to all of the other forms of molecular damage that degrade cell and tissue function? We will probably not gain an answer to that question until such time as a therapy to eliminate progerin is deployed and then tested in old people as well as in progeria patients. The example here is most likely not that therapy: I would expect disabling lamin A entirely to cause more harm than help in old people who only exhibit small amounts of progerin.

With an early onset and fast progression, progeria is one of the most severe forms of a group of degenerative disorders caused by a mutation in the LMNA gene. Both mice and humans with progeria show many signs of aging, including DNA damage, cardiac dysfunction, and dramatically shortened life span. The LMNA gene normally produces two similar proteins inside a cell: lamin A and lamin C. Progeria shifts the production of lamin A to progerin. Progerin is a shortened, toxic form of lamin A that accumulates with age and is exacerbated in those with progeria.

The researchers utilized the CRISPR/Cas9 system to deliver the gene therapy into the cells of the progeria mouse model expressing Cas9. An adeno-associated virus (AAV) was injected containing two synthetic guide RNAs and a reporter gene. The guide RNA ushers the Cas9 protein to a specific location on the DNA where it can make a cut to render lamin A and progerin nonfunctional, without disrupting lamin C. The reporter helps researchers track the tissues that were infected with the AAV.

Two months after the delivery of the therapy, the mice were stronger and more active, with improved cardiovascular health. They showed decreased degeneration of a major arterial blood vessel and delayed onset of bradycardia (an abnormally slow heart rate) - two issues commonly observed in progeria and old age. Overall, the treated progeria mice had activity levels similar to normal mice, and their life span increased by roughly 25 percent.

Towards Universal Cell Lines and Tissues Grown from Induced Pluripotent Stem Cells

There is an enormous difference in logistics and cost between cell therapies that must use a patient's own cells and cell therapies that arise from a single universal cell line that can be used in any patient. While in principle it is perfectly possible to reprogram a patient's cells into induced pluripotent stem cells, differentiate those cells into the desired cell type, and then even grow functional organoids, that all takes a lot of time and effort, and is as yet far from reliable. It would be much cheaper and much faster to have a factory producing cell lines and organs that can be universally used. When organs and other large tissue sections can be reliably grown from cells in the laboratory, this point will also apply there.

Given that, it is interesting to see signs of progress towards the production of induced pluripotent stem cells that lack the features that would cause a recipient immune system to attack them, but can nonetheless survive in the body. Achieving this goal is the basis for a much more cost-effective regenerative medicine and tissue engineering industry.

The immune system is unforgiving. It's programmed to eradicate anything it perceives as alien, which protects the body against infectious agents and other invaders that could wreak havoc if given free rein. But this also means that transplanted organs, tissues or cells are seen as a potentially dangerous foreign incursion, which invariably provokes a vigorous immune response leading to transplant rejection. When this occurs, donor and recipient are said to be - in medical parlance - "histocompatibility mismatched."

In the realm of stem cell transplants, scientists once thought the rejection problem was solved by induced pluripotent stem cells (iPSCs), which are created from fully-mature cells - like skin or fat cells - that are reprogrammed in ways that allow them to develop into any of the myriad cells that comprise the body's tissues and organs. If cells derived from iPSCs were transplanted into the same patient who donated the original cells, the thinking went, the body would see the transplanted cells as "self," and would not mount an immune attack. But in practice, clinical use of iPSCs has proven difficult. For reasons not yet understood, many patients' cells prove unreceptive to reprogramming. Plus, it's expensive and time-consuming to produce iPSCs for every patient who would benefit from stem cell therapy.

Scientists wondered whether it might be possible to sidestep these challenges by creating "universal" iPSCs that could be used in any patient who needed them. In their new paper, they describe how after the activity of just three genes was altered, iPSCs were able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems. The researchers first used CRISPR to delete two genes that are essential for the proper functioning of a family of proteins known as major histocompatibility complex (MHC) class I and II. MHC proteins sit on the surface of almost all cells and display molecular signals that help the immune system distinguish an interloper from a native. Cells that are missing MHC genes don't present these signals, so they don't register as foreign. However, cells that are missing MHC proteins become targets of immune cells known as natural killer (NK) cells.

The team found that CD47, a cell surface protein that acts as a "do not eat me" signal against immune cells called macrophages, also has a strong inhibitory effect on NK cells. Believing that CD47 might hold the key to completely shutting down rejection, the researchers loaded the CD47 gene into a virus, which delivered extra copies of the gene into mouse and human stem cells in which the MHC proteins had been knocked out. CD47 indeed proved to be the missing piece of the puzzle. When the researchers transplanted their triple-engineered mouse stem cells into mismatched mice with normal immune systems, they observed no rejection.


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