Fight Aging! Newsletter, October 8th 2018

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

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  • Commentary on Recent Research into Mitochondrial DNA and Aging
  • Addition of Macrophages Enables Lab Grown Muscle to Regenerate
  • Animal Data Shows Fisetin to be a Surprisingly Effective Senolytic
  • Across Large Populations, Telomere Length Falters as a Biomarker of Aging in the Oldest Cohorts
  • Senescent Cells in Skin Contribute to the Formation of Age Spots, and Can be Destroyed by Radiofrequency Treatment
  • Skin is Surprisingly Resilient to Cancer
  • There are No Mesenchymal Stem Cells
  • Dementia Correlates with a History of Hypertension
  • Idiopathic Pulmonary Fibrosis Patients Exhibit Greater Levels of Senescence in Bone Marrow Stem Cells
  • Life Biosciences: David Sinclair Aims to be a Major Player in the Present Generation of Commercial Longevity Science
  • Winners Announced for the Longevity Film Competition
  • Exercise Enhances the Cellular Maintenance Processes of Autophagy
  • Mesenchymal Stem Cell Aging as a Contributing Cause of Osteoporosis
  • Loss of Plasticity in the Brain with Age isn't a Simple One-Dimensional Decline
  • An Interview with James Peyer of Apollo Ventures

Commentary on Recent Research into Mitochondrial DNA and Aging

Today I'll point out a commentary on recent research in which a method of degrading mitochondrial function was shown to produce aspects of accelerated aging in mice. The commentary is somewhat more approachable than the paper it comments on. The challenge here is the same as in any form of research in which something vital is broken in animal biochemistry, and wherein the result looks a lot like a faster pace of aging. These forms of artificial breakage are almost never relevant to the understanding of normal aging; they create an entirely different state of metabolism and decline.

It is true that normal aging is a process of damage accumulation and reactions to that damage. But it is a specific mix of damage of specific types. That damage has the downstream consequence of loss of cell and tissue function, which in turn leads to the visible, well-known symptoms of aging and age-related disease. Near any form of significant damage and breakage in biochemistry will also lead to loss of cell and tissue function, however, even if it doesn't normally occur in the wild. Very high levels of unrepaired nuclear DNA damage, far greater than exist in normal animals, produce conditions that look a lot like accelerated aging. Consider Hutchinson-Gilford progeria syndrome as a natural example. But this doesn't tell us much about normal aging despite the fact that lower levels of nuclear DNA damage are a feature of normal aging.

In the research referenced in the commentary here, mitochondrial DNA is removed from cells, leaving them with an abnormally low count of genome copies in the mitochondrial population. The result looks a lot like accelerated aging. Mitochondria are the power plants of the cell, responsible for producing the chemical energy store molecules used to power all cellular processes. Progressive loss of function in mitochondria is implicated in aging and many age-related diseases, but just as in the case of raised levels of nuclear DNA damage, it isn't at all clear that artificial breakage of mitochondria tells us anything useful about the mitochondrial contribution to normal aging. It definitely tells us what happens when you break things, but any other insights are tenuous and highly dependent on the details.

Mitochondrial DNA keeps you young

Ageing is characterized by a decline in mitochondrial function, including a reduction in TCA cycle enzymes, a decrease in the respiratory capacity, and an increase in reactive oxygen species (ROS) production, in both animal models and humans. These alterations can lead to DNA mutations, cell death, inflammation, and a reduction in stem cell function, contributing to tissue degeneration. The increase in mitochondrial DNA mutations observed in aged mitochondria from both mouse models and humans is the proposed driving force.

Mitochondrial DNA (mtDNA) is replicated by a dedicated mitochondrial DNA polymerase (DNA pol γ), whose proofreading activity has been ablated to generate a mouse model, i.e., the so-called "mitochondrial mutator mouse", able to introduce random mutations in mtDNA. This model displays a strong ageing phenotype, including hair loss, graying, and kyphosis, along with reduced mitochondrial respiratory complex activity and increased oxidative stress.

Researchers have recently described a novel transgenic mouse with an inducible depletion of mtDNA, i.e., the mtDNA-depleter mouse. This model carries an aspartate to alanine conversion at position 1135 of POLG1 that behaves as a dominant negative for DNA pol γ, whose expression is under the control of a Tet-responsive promoter. Doxycycline administration leads to the induction of mutant DNA pol γ that blocks mtDNA replication. As mtDNA is removed by mitophagy for recycling, the activation of the transgene leads to a reduction of more than 60% in the total mtDNA content after 2 months. As mtDNA codes the core subunits of mitochondrial respiratory complexes, a significant impairment was observed in their activity.

At the macroscopic level, the mtDNA-depleter mouse shows expected accelerated ageing, including weight loss and kyphosis, but ageing of the skin was particularly severe and characterized by hair loss, wrinkles, and pigmentation, while at the histological level, this mouse displayed hyperplastic and hyperkeratotic epidermis, degeneration of hair follicles and extensive inflammatory infiltrates. Although the model requires extensive additional characterization, histological sections of other tested tissues (considered to have a high demand for mitochondrial activity), including the liver, brain and myocardium, do not display major alterations.

How mtDNA depletion affects ageing is a rather interesting question. The extended inflammatory infiltrates suggest that mitochondria could produce ROS as ROS can act as signaling molecules for inflammasome activation; unfortunately, the author did not report measurements of oxidative stress, but cells depleted of mtDNA are usually characterized by diminished oxygen consumption and ROS production, suggesting that oxidative stress should not mediate the ageing phenotype observed here. However, the following two major consequences were observed in a cell model of mtDNA depletion using the same strategy as that used in the depleter mouse: (1) a significant rearrangement of histone acetylation due to indirect alterations in the citrate levels, and (2) a reduction in cell proliferation due to a reduction in the membrane potential and destabilization of Hif1a. While the type of epigenetic rearrangement that occurs during ageing is unclear, Hif1a depletion has been shown to lead to an accelerated aged skin phenotype in mice.

Another extremely interesting point in this study is the recovery of the phenotype. Halting doxycycline exposure led to a surprising and almost complete recovery of the mtDNA content and skin phenotype after one month. The recovery of the mtDNA content is expected since the original mtDNA was not completely exhausted. The recovery of the skin phenotype is more intriguing. The mutator mouse model provided important insight into how mitochondria can induce an ageing phenotype by affecting haematopoietic and neural stem cell self-renewal capacities. We speculate that mtDNA depletion affects epidermal stem cell function, leading to skin ageing. Although it has long been thought that stem cells do not rely on mitochondrial function (at least for ATP production), additional observations in adult stem cells from other tissues suggest that mitochondria can be fundamental for stem cell self-renewal. However, progenitor cells, which have an established dependency on mitochondrial respiration in many models, could be more sensitive to mtDNA depletion and therefore responsible for the rapid recovery.

Addition of Macrophages Enables Lab Grown Muscle to Regenerate

A good amount of evidence has been assembled by the scientific community to demonstrate that the innate immune cells called macrophages play a central role in tissue regeneration. Regeneration is an intricate dance of signaling between numerous cell types and cell states: stem cells, somatic cells, immune cells, and others. Macrophages supply necessary signals that help to guide regenerative processes. They are also responsible for destroying the temporary population of senescent cells that arises in wounds, cells that also deliver signals that promote regenerative activity. Senescent cells are useful in the short term, but if they linger they become disruptive and harmful.

One of the lines of evidence for the importance of macrophages in healing involves comparisons with species capable of highly proficient regeneration. In salamanders, regeneration of organs is dependent on the presence of macrophage signaling. Similarly, African spiny mice exhibit an unusually comprehensive regenerative capacity for mammals, and here again that is due to their macrophages.

Much of the investigative work on macrophages and regeneration has focused on muscle tissue, and the materials noted here today continue that theme. Researchers have been able to engineer small sections of functional muscle tissue for a number of years, with the inability to reliably produce capillary networks being the primary roadblock to the creation of large muscle sections for transplantation. Blood and nutrients can only perfuse through a few millimeters of solid tissue. These small organoids may be functional when it comes to the core capabilities of muscle tissue, but they are lacking when it comes to regenerative capacity. One logical approach to fixing this problem is to incorporate macrophages into the mix of cells, and judging from the results here, this works fairly well once the initial hurdles are overcome.

Macrophages enable regeneration of lab-grown adult muscle tissue

In 2014, researchers debuted the world's first self-healing, lab-grown skeletal muscle. The milestone was achieved by taking samples of muscle from rats just two days old, removing the cells, and "planting" them into a lab-made environment perfectly tailored to help them grow. For potential applications with human cells, muscle samples would be mostly taken from adult donors rather than newborns. There's just one problem - lab-made adult muscle tissues do not have the same regenerative potential as newborn tissue. "I spent a year exploring methods to engineer muscle tissues from adult rat samples that would self-heal after injury. Adding various drugs and growth factors known to help muscle repair had little effect, so I started to consider adding a supporting cell population that could react to injury and stimulate muscle regeneration. That's how I came up with macrophages, immune cells required for muscle's ability to self-repair in our bodies."

After a muscle injury, one class of macrophages shows up on the scene to clear the wreckage left behind, increase inflammation and stimulate other parts of the immune system. One of the cells they recruit is a second kind of macrophage, dubbed M2, that decreases inflammation and encourages tissue repair. While these anti-inflammatory macrophages had been used in muscle-healing therapies before, they had never been integrated into a platform aimed at growing complex muscle tissues outside of the body. "When we damaged the adult-derived engineered muscle with a toxin, we saw no functional recovery and muscle fibers would not build back. But after we added the macrophages in the muscle, we had a wow moment. The muscle grew back over 15 days and contracted almost like it did before injury. It was really remarkable."

The discovery may lead to a new line of research for potential regenerative therapies. According to a popular theory, fetal and newborn tissues are much better at healing than adult tissues at least in part because of an initial supply of tissue-resident macrophages that are similar to M2 macrophages. As individuals age, this original macrophage supply is replaced by less regenerative and more inflammatory macrophages coming from bone marrow and blood. "We believe that the macrophages in our engineered muscle system may behave more like the muscle-resident macrophages people are born with. We are currently working to understand if this is indeed the case. One could then envision 'training' macrophages to be better healers in a system like ours or augmenting them by genetic modifications and then implanting them into damaged sites in patients."

Incorporation of macrophages into engineered skeletal muscle enables enhanced muscle regeneration

Adult skeletal muscle has a robust capacity for self-repair, owing to synergies between muscle satellite cells and the immune system. In vitro models of muscle self-repair would facilitate the basic understanding of muscle regeneration and the screening of therapies for muscle disease. Here, we show that the incorporation of macrophages into muscle tissues engineered from adult-rat myogenic cells enables near-complete structural and functional repair after cardiotoxic injury in vitro.

First, we show that-in contrast with injured neonatal-derived engineered muscle-adult-derived engineered muscle fails to properly self-repair after injury, even when treated with pro-regenerative cytokines. We then show that rat bone-marrow-derived macrophages or human blood-derived macrophages resident within the in vitro engineered tissues stimulate muscle satellite cell-mediated myogenesis while significantly limiting myofibre apoptosis and degeneration. Moreover, bone-marrow-derived macrophages within engineered tissues implanted in a mouse model augmented blood vessel ingrowth, cell survival, muscle regeneration, and contractile function.

Animal Data Shows Fisetin to be a Surprisingly Effective Senolytic

It is exciting to see animal data arrive for some of the potentially senolytic compounds that may turn out to destroy enough senescent cells in mammals to be worth using as first generation rejuvenation therapies. As a reminder, the accumulation of senescent cells is one of the causes of aging; countless cells become senescent every day in our bodies, but near all are destroyed. A tiny fraction linger to cause significant harm through the inflammatory signal molecules that they secrete. If these errant cells can be removed, then inflammatory diseases and numerous aspects of aging can be turned back to some degree. The results in mice stand head and shoulders above all of the other approaches to aging in terms of reliability and breadth of benefits.

Some senolytic compounds have been tested in animals, but a larger body of candidate senolytic drugs are presently only accompanied by cell study data. The ability to selectively destroy senescent cells in a petri dish does little more than indicate potential; there is a significant rate of failure in medical research and development for compounds with promising cell data, and any number of reasons as to why they may not work well enough in tissues or otherwise turn out to be infeasible for use in animals and humans. Fisetin was one such senolytic candidate with cell study data only, and I had not viewed it as a likely prospect. It is a flavonoid, and the one other well-known possibly senolytic flavonoid turned out not to be useful on its own - though it is helpful as a part of a combination treatment.

Given that, results from the recent animal study of fisetin noted here greatly exceed expectations, surprisingly so. Fisetin appears about as effective in mice as any of the current top senolytics, such as the chemotherapeutics dasatinib and navitoclax. Per the data in the open access paper below, dosing with fisetin destroys 25-50% of senescent cells depending on organ and method of measurement. The dose level is large in absolute terms, as one might expect for a flavonoid. For aged mice and a one-time treatment, the researchers used 100 mg/kg daily for five days. The usual approach to scale up estimated doses from mouse studies to initial human trials leads to 500 mg per day for five days for a 60kg human.

Given the wealth of new results emerging these days, it seems to me that people focused on self-experimentation, open human trials, and investigative mouse studies in this field should be moving to focus on combination therapies. Consider a combination of fisetin, dasatinib, quercetin, piperlongumine, and FOXO4-DRI - multiple different mechanisms to provoke apoptosis that are all hitting senescent cells at the same time. The goal would be to see if it is possible to engineer a significantly higher level of clearance of senescent cells than any of these senolytics can achieve on their own. This seems like a plausible goal, and may turn out to present meaningful competition to efforts such as those of Oisin Biotechnologies and other groups developing more sophisticated senolytic therapies that should have high rates of clearance.

Researchers Have Discovered How to Slow Aging

As people age, they accumulate damaged cells. When the cells get to a certain level of damage they go through an aging process of their own, called cellular senescence. The cells also release inflammatory factors that tell the immune system to clear those damaged cells. A younger person's immune system is healthy and is able to clear the damaged cells. But as people age, they aren't cleared as effectively. Thus they begin to accumulate, cause low-level inflammation and release enzymes that can degrade the tissue.

Researchers found a natural product, called fisetin, reduces the level of these damaged cells in the body. They found this by treating mice towards the end of life with this compound and see improvement in health and lifespan. "These results suggest that we can extend the period of health, termed healthspan, even towards the end of life. But there are still many questions to address, including the right dosage, for example." One question they can now answer, however, is why haven't they done this before? There were always key limitations when it came to figuring out how a drug will act on different tissues, different cells in an aging body. Researchers didn't have a way to identify if a treatment was actually attacking the particular cells that are senescent, until now.

Fisetin is a senotherapeutic that extends health and lifespan

A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated.

Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.

Across Large Populations, Telomere Length Falters as a Biomarker of Aging in the Oldest Cohorts

Telomeres are the repeated DNA sequences found at the ends of chromosomes. A little of that length is lost with each cell division, and this serves as a part of the mechanism that limits the number of times a somatic cell can divide. Stem cells employ telomerase to maintain long telomeres through the asymmetric divisions needed to supply tissues with new daughter somatic cells equipped with long telomeres. This split of responsibilities between many restricted cells and a few privileged cells is the primary strategy by which multicellular organisms keep the risk of cancer low enough for evolutionary success.

Given this arrangement, average telomere length in any given tissue is a blurred measure of how fast cells divide and how frequently new cells are delivered by the supporting stem cell population. Over large populations of people, shorter telomere length tends to correlate with greater age, most likely because stem cell activity declines with age. Unfortunately, it is the case that telomere length as presently measured - in leukocytes from a blood sample - is quite dynamic in response to day to day environmental circumstance, and is thus only poorly correlated to aging for any given individual. Telomere measurement services are readily available, but there really isn't all that much that can be deduced from the result. It isn't actionable. If measured again next week or next month, or with a passing infection versus without, then the number will likely be significantly different.

Further, for every study population in which the correlation with aging is affirmed, there is another in which the telomere length data stubbornly refuses to do the expected thing. The study here produces both of these outcomes, confirming the correlation in younger people, but also finding that the relationship falters for individuals older than 80 years of age. All in all telomere length just isn't a very useful measure of aging. It is not robust enough, and its individual variability means that the numbers are next to useless when it comes to guiding medical decisions.

Telomere Length and All-Cause Mortality: A Meta-analysis

Telomere attrition has been widely reported to be associated with increased morbidity and mortality of various age-related diseases. In 2003 was reported for the first time that telomere shortening contributed to all-cause mortality based on a study of 143 unrelated Utah residents aged 60-97 years. More recently, other researchers used the largest study so far (n = 64,637) to demonstrate that short telomeres were associated with a higher risk of all-cause mortality. Although several other studies reported an association of telomere length (TL) with all-cause mortality, there is a substantial variability among the findings of these studies due to the different TL measurement techniques and the varying age, sex, and ethnicity of the study participants. To this end, we aimed to perform a meta-analysis of the association of TL with all-cause mortality, taking advantage of both previously published results from cohort studies of the general population and un-published original data from the Swedish Twin Registry (STR).

We found that shorter leukocyte TL was associated with an increased risk of all-cause mortality, although some between-study heterogeneity was observed. The magnitude of the association of TL and all-cause mortality was similar for the youngest groups (younger than 75 years and 75-80 years), but weaker for the oldest old (over 80 years). The results of our STR cohorts were similar in effect sizes compared to several earlier studies, but slightly weaker than those reported by others.

Women have on average longer telomeres and life expectancy compared to men of the same age. Our STR study further confirmed the sex difference in TL. Several plausible biological mechanisms have been proposed to explain the phenomenon. First, estrogen may stimulate the production of telomerase and may be protective against reactive oxygen species damage. In addition, estrogens have been shown to stimulate the phosphointositol 3-kinase/Akt pathway, which contributes to enhanced telomerase activity. Second, the heterogametic sex hypothesis suggests that shorter telomeres in men may arise if the unguarded X chromosome in men contains inferior telomere maintenance alleles. Third, men have a faster rate of telomere attrition than women although there is no difference of TL at birth. The longer telomeres may on the other hand be a reason for the overall lower risk of age-related diseases and consequently longer lifespan of women compared to men.

Senescent Cells in Skin Contribute to the Formation of Age Spots, and Can be Destroyed by Radiofrequency Treatment

Two quite interesting findings are presented in this open access paper. Firstly, the pigmented areas of skin called age spots are in large part generated by the presence of senescent cells and their detrimental effects on mechanisms of skin pigmentation. Secondly, one the skin treatments that has for years been touted as rejuvenating by vendors in the more dubious, unscientific end of the medical community in fact destroys a fair number of senescent cells and therefore might actually be a legitimate rejuvenation therapy, albeit limited to the skin. This is certainly a novelty, but I suppose that the research community might find more such cases as the understanding of senescent cells in aging continues to grow in detail and sophistication. There will be a certain amount of up-ending of expectations on all sides as rejuvenation therapies and their associated research communities make progress in the years to come.

A caveat on this research is that the portion using human data involves results obtained from only a few individuals, while much of the mechanistic examination in cells and tissues largely uses senescence induced in non-physiological conditions. Based on other research, cells made senescent in various non-physiological ways can differ in state significantly from those that arise naturally in the body. They are more or less vulnerable to different senolytics, for example. Still, this work is intriguing, a good start, and plausible when taken as a whole. I wouldn't be overly surprised to find it validated when a more extensive study is undertaken. One possible approach to independent confirmation is for the groups working on human trials of senolytic drugs to start paying attention to the age spots of their patients. This could be accomplished without excessive additional cost: a photographic record of hands and forearms, for example.

Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo

Pigmentation is an outcome of the interplay between melanocytes and neighbouring cells, such as keratinocytes and fibroblasts. Cutaneous ageing is an important extrinsic process that modifies the pigmentary system. Senile lentigo, also known as age spots, is one of the major changes associated with laxity and wrinkling during the ageing of skin. It is characterized by the presence of hyperpigmented spots in the elderly.

Cellular senescence is a fundamental ageing mechanism. Senescent cells and those with the related senescence-associated secretory phenotype (SASP) are known to be the main drivers of the age-related phenotype. During intrinsic and extrinsic skin ageing, the skin can contain senescent cells in epidermal and dermal compartments. Cellular senescence has been studied in dermal fibroblasts, which secrete factors that contribute to skin wrinkling. For example, the chronic secretion of matrix metalloproteinases by senescent cells is an important contributor to the degradation of collagen and other extracellular matrix components in dermal tissue. A decrease in the expression of transforming growth factor type II receptor appeared to be a critical event in age-related skin thinning. However, despite the important role exerted by neighbouring cells on the regulation of melanocyte biology, few studies have examined how senescent cells are involved in skin pigmentation, and it remains unclear whether senescent cells affect nearby epidermal melanocytes and influence ageing pigmentation.

In this study, we reveal what we believe is a novel mechanism whereby aged fibroblasts contribute to the local regulation of melanogenesis. We show that as an individual ages, pigmented skin contains an increasing proportion of senescent fibroblasts. Phenotype switching in these cells results in the loss of SDF1, and SDF1 deficiency appears to be a potent stimulus for the melanogenic processes that contribute to uneven pigmentation. These changes might be epigenetic. For example, the level of hypermethylation of the SDF1 promoter was remarkably different between hyperpigmented and perilesional skin.

The human skin, unlike other organs, undergoes photo-ageing in addition to natural ageing processes, and photo-ageing has been attributed to ageing pigmentation. Both processes are cumulative, and the most noticeable age-related changes therefore occur in the superficial layer of the skin. In the present study, we show that cellular senescence is especially likely to occur in fibroblasts located in the upper dermis of pigmented skin. Senescent fibroblasts are expected to influence melanocytes via cross-talk that can readily occur through a damaged basement membrane. We showed that senescent fibroblasts play a stimulatory role in pigmentation by upregulating the expression of the melanogenesis regulators MITF and tyrosinase in melanocytes.

Moreover, the impact of senescent fibroblasts on skin pigmentation was directly demonstrated when eliminating senescent cells with an intervention that reduced pigmentation. Microneedle fractional radiofrequency (RF) is a cosmetic therapy that induces skin rejuvenation via electromagnetic thermal injury. The microneedle RF device was chosen to manipulate only dermal cells, in which the microneedles generate thermal coagulation columns in the dermis, not in the epidermis. It was previously demonstrated that fractional laser treatment decreases the occurrence of senescent fibroblasts in aged dermis. Ten volunteers with senile lentigo were treated with RF, and skin samples were collected from 4 participants who agreed to undergo a skin biopsy before and at 6 weeks after treatment. Following RF treatment, the number of senescent fibroblasts was significantly reduced. The elimination of these cells was thought to be caused by RF-induced cell death. The elimination of senescent fibroblasts from senile lentigo was accompanied by skin lightening.

Skin is Surprisingly Resilient to Cancer

Human skin has evolved a greater resilience to cancer than other tissue types. It is an outcome that makes a certain amount of sense, given that skin is exposed to the additional mutational burden caused by solar radiation. Researchers here investigate some of the mechanisms involved in this cancer resistance, and suggest that the level of mutational damage is high enough that potentially cancerous mutations are continually being outcompeted by other potentially cancerous mutations. It is rare for any one mutant lineage to dominate sufficiently to generate skin cancer. The goal in this sort of investigation is to find something that could potentially serve as the basis for a cancer treatment. While this is fascinating, I don't immediately see the potential for any practical use of these findings.

Non-melanoma skin cancer in humans includes two main types: basal cell skin cancer and squamous cell skin cancer, both of which develop in areas of the skin that have been exposed to the sun. Basal cell skin cancer is the most common type of skin cancer, whereas squamous cell skin cancer is generally faster growing. However, every person who has been exposed to sunlight carries many mutated cells in their skin, and only very few of these may develop into tumours. The reasons for this are not well understood.

For the first time, researchers have shown that mutated cells in the skin grow to form clones that compete against each other. Many mutant clones are lost from the tissue in this competition, which resembles the selection of species that occurs in evolution. Meanwhile, the skin tissue is resilient and functions normally while being taken over by competing mutant cells.

Scientists used mice to model the mutated cells seen in human skin. Researchers focused on the p53 gene, a key driver in non-melanoma skin cancers. The team created a genetic 'switch', which when turned on, replaced p53 with the identical gene including the equivalent of a single letter base change. This changed the p53 protein and gave mutant cells an advantage over their neighbours. The mutated cells grew rapidly, spread and took over the skin tissue, which became thicker in appearance. However, after six months the skin returned to normal and there was no visual difference between normal skin and mutant skin.

The team then investigated the role of sun exposure on skin cell mutations. Researchers shone very low doses of ultraviolet light (below sunburn level) onto mice with mutated p53. The mutated cells grew much faster, reaching the level of growth seen at six months in non-UV radiated clones in only a few weeks. However, despite the faster growth, cancer did still not form after nine months of exposure. "In humans, we see a patchwork of mutated skin cells that can expand enormously to cover several millimetres of tissue. But why doesn't this always form cancer? Our bodies are the scene of an evolutionary battlefield. Competing mutants continually fight for space in our skin, where only the fittest survive. We did not observe a single mutant colony of skin cells take over enough to cause cancer, even after exposure to ultraviolet light. Exposure to sunlight continually created new mutations that outcompeted the p53 mutations."

There are No Mesenchymal Stem Cells

A growing number of researchers are arguing that the term "mesenchymal stem cell" has broadened to the point of uselessness, and now serves to obscure significant differences in cell populations. This is a similar situation to that of the long-running discussion regarding very small embryonic-like stem cells, another term of art that probably lumps together a broad selection of quite different cell types. Since mesenchymal stem cells, whatever they might be in each individual case, are now widely used in therapy it seems a little more pressing to resolve questions of cell identity here, however. To what degree are varied results from treatments an outcome of failing to adequately categorize cell phenotypes and sources? Mesenchymal stem cell transplantation is a reliable way to reduce chronic inflammation, but any other outcome, such as some degree of tissue regeneration, is by no means assured.

Various populations of cells in the adult human body have been the subject of controversy since the early 2000s. Contradictory findings about these haphazardly termed 'mesenchymal stem cells', including their origins, developmental potential, biological functions and possible therapeutic uses, have prompted biologists, clinicians and scientific societies to recommend that the term be revised or abandoned. Last year, even the author of the paper that first used the term mesenchymal stem cells (MSCs) called for a name change.

Tissue-specific stem cells, which have a limited ability to turn into other cell types, are the norm in most of the adult body. Several studies indicate that the variety of cells currently dropped into the MSC bucket will turn out to be various tissue-specific cell types, including stem cells. Yet the name persists despite the evidence pointing to this, and almost two decades after questions about the validity of MSCs were first raised. A literature search indicates that, over the past 5 years, more than 3,000 research articles referring to MSCs have been published every year.

In our view, the wildly varying reports have helped MSCs to acquire a near-magical, all-things-to-all-people quality in the media and in the public mind - hype that has been easy to exploit. MSCs have become the go-to cell type for many unproven stem-cell interventions. The confusion must be cleared up. What is needed is a coordinated global effort to improve understanding of the biology of the cells currently termed MSCs, and a commitment from researchers, journal editors, and others to use more precise labels. We must develop standardized analyses of gene expression, including on a cell-by-cell basis, and rigorous assays to establish the precise products of cell differentiation in various tissues. Such efforts could put an end to lingering questions about MSC identity and function, once and for all.

Dementia Correlates with a History of Hypertension

Hypertension, raised blood pressure, is an important mediating mechanism in aging. It is caused by forms of low-level biochemical damage in and around the cells of blood vessel walls, and produces structural damage to organs and the cardiovascular system, leading to dysfunction and death. Hypertension is sufficiently harmful in and of itself that present methods of reducing blood pressure can reduce risk of mortality and clinical age-related disease, even given significant side-effects, and even given that none of these methods address the root causes of hypertension. They override reactions to damage rather than repairing damage. Repair of that damage, once implemented, should prove far more effective.

One of the ways in which hypertension damages organs is through an increased pace of rupture in capillaries and other forms of small-scale structural damage. This is particularly important in the brain, as it has only a very limited capacity to heal injuries of this nature. Cognitive decline driven by hypertension is in part a progression of tiny, unnoticed strokes, each destroying the function of a minuscule portion of the brain. Over time that adds up, and thus we might expect to observe correlations between hypertension and dementia. Nothing is simple in human data, of course, as even straightforward relationships can be challenging to extract from the very noisy data.

Hypertension is a highly prevalent condition, occurring in one-third of the world's adults and in two-thirds of adults over 65 years of age. Both hypertension and dementia are age-related comorbidities which may induce considerable disabilities. Some epidemiological studies showed that hypertension is an important risk factor of dementia, which was evident from the positive relationship between blood pressure at midlife and the subsequently higher risk of cognitive impairment or dementia late in life; however, some other studies provided contradictory evidence that low blood pressure was a risk factor for dementia and cognitive decline.

We, therefore, intend to explore the association between blood pressure and cognition. Data were drawn from 3,327 participants at the baseline of Shanghai Aging Study. History of hypertension was inquired and confirmed from participants' medical records. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in the early morning. Participants were diagnosed with "cognitive normal," "mild cognitive impairment (MCI)," or "dementia" by neurologists. Multivariate logistic regression was used to evaluate the association between history of hypertension, duration of hypertension, SBP, DBP, or classification of blood pressure and cognitive function.

Our study indicated that history of hypertension, duration of hypertension, and high blood pressure were positively associated with dementia. A significantly higher proportion of hypertension [76.5%] was found in participants with dementia than in those with MCI [59.3%] and cognitive normal [51.1%]. Participants with dementia had significantly higher SBP [157.6 mmHg] than those with MCI [149.0 mmHg] and cognitive normal [143.7 mmHg]. After adjusting for sex, age, education, living alone, body mass index, anxiety, depression, heart disease, diabetes, and stroke, the likelihood of having dementia was positively associated with history of hypertension (odds ratio = 2.10), duration of hypertension (odds ratio = 1.02 per increment year), higher SBP (odds ratio = 1.14 per increment of 10 mmHg), higher DBP (odds ratio = 1.22 per increment of 10 mmHg), moderate hypertension (odds ratio = 2.09), or severe hypertension (odds ratio = 2.45).

Idiopathic Pulmonary Fibrosis Patients Exhibit Greater Levels of Senescence in Bone Marrow Stem Cells

Idiopathic pulmonary fibrosis (IPF) appears to be significantly driven by the presence of senescent cells in the lungs. Other forms of fibrosis in other organs have been similarly linked to senescent cells. Increased cellular senescence is a feature of aging, and indeed is one of the root causes of aging. These cells secrete a potent mix of signals that induce inflammation, damage tissue structures, and change the behavior of nearby cells for the worse. In this context the results presented here are intriguing; the authors of this open access paper find that IPF patients have more senescent bone marrow stem cells.

There are a few ways to think about this. The first is that aging is a global phenomenon of accumulating molecular damage throughout the body, and people with enough damage to be predisposed to clinical levels of lung fibrosis are going to exhibit more pronounced measures of aging everywhere else as well. The second is that stem cells are negatively affected by high levels of inflammation, inflammatory signaling can spread widely by following the circulatory system, and the inflammatory conditions of IPF in lung tissues may thus be harming stem cell populations throughout the body. Lastly, one could argue causation in the other direction, as the researchers do here, suggesting that senescence of stem cells in bone marrow is a contributing factor to the development of IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by a progressive and irreversible loss of lung function though accumulation of scar tissue. Aging is considered the main risk factor for IPF. Along with others, we have demonstrated that there is an increase in markers of cell senescence in lung fibroblasts from IPF patients. Additionally, we have shown that, in animal models of lung injury, aged bone marrow-derived mesenchymal stem cells (B-MSCs) have decreased protective activity. This is in contrast to what we had previously described in young animal models of pulmonary fibrosis, where infusion of B-MSCs isolated from normal young donors in the initial stages of the injury results in a decrease in collagen deposition in the lung.

Therefore, we aimed to determine the differences in the biological and functional characteristics of B-MSCs from healthy individuals and IPF patients within the same age range. Characterization of IPF B-MSCs shows an increase in cell senescence linked to an upsurge of senescence-associated secretory phenotypes (SASPs) promoting a proinflammatory milieu and increasing deposition of components from the extracellular matrix. Our data suggest that extrapulmonary alterations in B-MSCs from IPF patients might contribute to the pathogenesis of the disease.

The consequences of having senescent B-MSCs are not completely understood, but the decrease in their ability to respond to normal activation and the risk of having a negative impact on the local niche by inducing inflammation and senescence in the neighboring cells suggests a new link between B-MSC and the onset of the disease.

Life Biosciences: David Sinclair Aims to be a Major Player in the Present Generation of Commercial Longevity Science

This article, unfortunately paywalled, is interesting to note as a mark of the now increasingly energetic expansion of commercial efforts in longevity science. David Sinclair has been building a private equity company to work in many areas relevant to this present generation of commercial longevity science; while I'm not sold on his primary research interests as the basis for meaningful treatments for aging, he is diversifying considerably here, including into senolytics, the clearance of senescent cells demonstrated to produce rejuvenation in animal studies. This sort of approach to business mixes aspects of investing and running a company; it allows a fair degree of flexibility if well run. For someone with comparatively easy access to large amounts of capital, it is a sensible choice. The obvious other example in our field is Juvenescence, Jim Mellon's vehicle. We should expect to see many more entities of this nature arise as the message spreads that the first rejuvenation therapies actually work, and that treating aging as a medical condition is a viable near term goal.

Life Biosciences LLC, the longevity startup founded by Harvard researcher David Sinclair and funded by WeWork's Adam Neumann, is ramping up an expansion of its bid to become the world's largest company dedicated to antiaging drugs. Launched publicly in April, the company has six subsidiaries across four continents. Adding to that, it just acquired Lua Technologies Inc., a health-care communications company, to power Life Biosciences' research collaboration platform. To continue global expansion efforts, Life Biosciences is also looking to raise up to 25 million in new financing, according to a regulatory filing.

Some of the most heavily funded longevity startups like Unity Biotechnology, now public, focus on just one or a few aging-related diseases like osteoarthritis and vision loss. Life Biosciences is aiming for an all-encompassing gambit: to own all the best research, drug-development pipelines, intellectual property, and financing opportunities for the entire sector.

For the past three years, the company has operated quietly amid a surge of activity from other venture-backed longevity startups. In the past year, Life Biosciences' workforce has grown to 90 employees, including the hiring of several veteran pharmaceutical and IT executives into key leadership positions. "Our thesis was to have a land grab of the best people before we let ourselves be known and have competition. We have achieved that now." Life Biosciences has secured several prominent aging and longevity researchers including Dr. Nir Barzilai.

Life Biosciences' portfolio covers a range of longevity research and therapeutics including drugs to target metabolic diseases like diabetes, the use of stem cells to aid in senescent, or so-called "zombie" cell removal, and compounds to prolong life for pets. Two of Life Biosciences' current companies, Senolytic Therapeutics Inc. and Jumpstart Fertility Inc., were acquired at a very early stage while the other four were formed in-house.

Winners Announced for the Longevity Film Competition

The winners of the recent Longevity Film Competition have been announced, and their videos can be watched at the competition website. Congratulations are due to the contestants. It is a pleasure to see that our community of advocacy and support for rejuvenation research has grown in recent years to the point at which a short contest of this nature can produce a variety of quality entries. We have come a long way since the turn of the century, and our early struggles to find funding and fellow travelers on the road to an end to aging are but a memory now. Popular culture is already forgetting just how opposed people were to the idea of extending healthy life spans, now that the first rejuvenation therapies have been shown to work in animal studies. There is a long way yet to go, but with greater funding and greater popular support, we are moving much faster now.

The Longevity Film Competition is an initiative by the Healthy Life Extension Society, the SENS Research Foundation, and the International Longevity Alliance. The promoters of the competition invited filmmakers everywhere to produce short films advocating for healthy life extension, with a focus on dispelling four usual misconceptions and concerns around the concept of life extension: the false dichotomy between aging and age-related diseases, the Tithonus error, the appeal to nature fallacy, and the fear of inequality of access to rejuvenation biotechnologies.

The competition is now over; the deadline for submissions was September 15, and fittingly, the winners have been announced today, October 1, in occasion of Longevity Day. "I want to say that this was a big challenge. The creators have used very different techniques and tools, which made most of the videos in the shortlist very hard to compare. Each video has its own advantages, and I can't help but congratulate every team on their personal success in delivering the message! This year's shortlist is a wonderful collection of perfectly unique stories."

Exercise Enhances the Cellular Maintenance Processes of Autophagy

How does exercise improve health over the long term and modestly extend healthspan? One of the important mechanisms is increased autophagy, the collection of cellular maintenance processes that are provoked into action by various stresses. Heat, lack of nutrients, and the oxidative molecules generated during the hard work of exercise are all sufficient to trigger greater autophagy for some period of time, continuing even after the stress has ended. This sort of stress response is an important component of near all of the methods demonstrated to somewhat slow aging in laboratory species. Sadly it isn't anywhere near as effective at extending life span in longer-lived species such as our own. Nonetheless, the benefits of exercise are both highly reliable and essentially free. It would be foolish to skip them given that cost-benefit equation.

Researchers have found that a lack of muscle stimulus due to a surgically induced sciatic nerve injury in rats resulted in a buildup of inadequately processed proteins in muscle cells and consequently led to muscle weakness or wasting. This buildup was caused by the impairment of autophagy, the cellular machinery responsible for identifying and removing damaged proteins and toxins. The researchers demonstrated that physical exercise can keep the autophagic system primed and facilitate its activity when necessary, as in the case of muscle dysfunction due to the lack of stimulus. The degenerative processes caused by a lack of muscle stimulus were found to be delayed in rats that had been subjected to a prior regime of aerobic exercise training.

"Daily exercise sensitizes the autophagic system, facilitating the elimination of proteins and organelles that aren't functional in the muscles. Removal of these dysfunctional components is very important; when they accumulate, they become toxic and contribute to muscle cell impairment and death. Imagine the muscles working in a similar manner to a refrigerator, which needs electricity to run. If this signal ceases because you pull the plug on the fridge or block the neurons that innervate the muscles, before long, you find that the food in the fridge and the proteins in the muscles will start to spoil at different speeds according to their composition. At this point, an early warning mechanism, present in cells but not yet in fridges, activates the autophagic system, which identifies, isolates and 'incinerates' the defective material, preventing propagation of the damage. However, if the muscle does not receive the right electric signal for long periods, the early warning mechanism stops working properly, and this contributes to cell collapse."

Mesenchymal Stem Cell Aging as a Contributing Cause of Osteoporosis

Bone tissue is constantly remodeled, broken down by osteoclasts and built up by osteoblasts. With age the balance of activity between these two cell populations shifts to favor osteoclasts. The result is ever weaker and more brittle bones, the condition known as osteoporosis. Numerous mechanisms may contribute to this cellular imbalance, with the signaling of senescent cells clearly implicated on the basis of recent evidence. The open access paper noted here looks another of the possible contributions, the aging of mesenchymal stem cells in the bone marrow.

Aging is a gradual process that results in a loss of tissue homeostasis, driving a progressive deterioration of tissue and organ functions mainly due to cellular damage accumulated throughout life. The human skeleton is especially affected by the passage of time: bone loss begins as early as the third decade of life, immediately after peak bone mass. In humans, bone is a highly active tissue which undergoes continuous self-regeneration throughout adulthood to maintain structural integrity in a process called bone remodeling. It has been estimated that the entire skeleton is remodeled every 10 years.

Throughout young adulthood more bone is formed than is resorbed, resulting in an increase in bone mass. Later on, throughout adulthood when the growth period is finished, the amount of resorbed bone equals that which is subsequently formed (remodeling balance). In the elderly, the amount of bone resorbed is greater than the amount of bone formed; accordingly, a decrease in bone mineral density occurs. As a consequence, bone aging is the main risk factor for primary osteoporosis, characterized by a reduction in bone mineral density, predisposing the elderly population to an increased risk of fractures.

Mesenchymal stem cells (MSCs) are non-hematopoietic stem cells which can be isolated from many tissues and have the capacity of self-renewal and to differentiate into various mesodermal cell types, such as osteoblasts, chondrocytes, and adipocytes. In bone, the process of osteogenesis is driven by a sequential cascade of biological processes initiated by the recruitment of MSCs to bone remodeling sites and subsequent proliferation. During the first steps of differentiation, MSCs proliferate and commit to actively proliferating pre-osteoblasts which do not secrete extracellular matrix (ECM). They further mature into non-proliferating osteoblasts involved in initial matrix secretion, maturation, and mineralization.

In the aging process, bone loss is caused not only by enhanced bone resorption activity but also by functional impairments of MSCs. At the cellular level, the MSC pool in the bone marrow niche shows a biased differentiation into adipogenesis at the cost of osteogenesis. This differentiation shift leads to decreased bone formation, contributing to the etiology of osteoporosis.

Loss of Plasticity in the Brain with Age isn't a Simple One-Dimensional Decline

Plasticity in the brain refers to the ability to generate new neurons and new connections between neurons. This is important for learning, memory, and recovery from damage. There is some question as to whether humans and mice are at all similar when it comes to the ability to generate new neurons in adulthood, but in either species overall plasticity declines with age, and this is thought to be an important contributing factor in cognitive decline. This decline isn't simple, however, as illustrated by the research results here. Like many aspects of aging, it may be more of a ragged dysregulation, a running awry of mechanisms that operated correctly in youth, rather than a matter of a process slowly and cleanly shutting down.

Neuroplasticity refers to the brain's ability to modify its connections and function in response to environmental demands, an important process in learning. Plasticity in the young brain is very strong as we learn to map our surroundings using the senses. As we grow older, plasticity decreases to stabilize what we have already learned. This stabilization is partly controlled by a neurotransmitter called gamma-Aminobutyric acid (GAB), which inhibits neuronal activity.

Researchers tested the hypothesis that plasticity stabilization processes become dysregulated as we age. They ran an experiment where rats were exposed to audio tones of a specific frequency to measure how neurons in the primary auditory cortex adapt their responses to the tones. They found that tone exposure caused neurons in older adult rats to become increasingly sensitized to the frequency, but this did not happen in younger adult rats. The effect in the older adult rats quickly disappeared after exposure, showing that plasticity was indeed dysregulated. However, by increasing the levels of the GABA neurotransmitter in another group of older rats, the exposure-induced plastic changes in the auditory cortex lasted longer.

These findings suggest the brain's ability to adapt its functional properties does not disappear as we age. Rather, they provide evidence that plasticity is, in fact, increased but dysregulated in the aged brain because of reduced GABA levels. Overall, the findings suggest that increasing GABA levels may improve the retention of learning in the aging brain. "Our work showed that the aging brain is, contrary to a widely-held notion, more plastic than the young adult brain. On the flip side, this increased plasticity meant that any changes achieved through stimulation or training were unstable: both easy to achieve and easy to reverse. However, we also showed that it is possible to reduce this instability using clinically available drugs. Researchers and clinicians may build upon this knowledge to develop rehabilitation strategies to harness the full plastic potential of the aging brain."

An Interview with James Peyer of Apollo Ventures

James Peyer of Apollo Ventures has a good sense of the biotechnology industry. If you are engaged in starting up a new biotechnology company, then he should be high on the list of folk to talk to while in the process of learning how it is that life science funding and development works in practice. The presently young longevity industry must initially fit into the existing life science ecosystem, even though it is destined to outgrow and eventually become enormously larger than that ecosystem. Half of humanity at any given time is the size of the market for rejuvenation therapies, vastly larger than the equivalent markets for any present medical technology intended to treat clinical disease after it emerges. Today just a handful of companies are taking the first steps in the creation of this ultimately gargantuan industry. Tomorrow comes the flood.

What turned you on to the field of anti-aging biology?

I became a scientist because I felt like we were treating the diseases of aging the wrong way. We were waiting for people to get cancer or Alzheimer's disease or something and then trying to do something about it, which felt totally backwards to me. By the time the diseases rear their heads they're at such a level of complexity that biologically, walking them backwards is an enormous - and maybe in many cases insurmountable - challenge.

We still don't know much about aging and how to stop it. Is it premature to start investing?

I think definitely not. Are we ready to administer new medicines to healthy people and help them live longer and prevent disease? The short answer is we're not there. But are new medicines that may eventually be able to do that ready to undergo clinical development for other diseases? Absolutely yes. And that's exclusively what Apollo works on.

What is your vision for Apollo?

Creating a portfolio approach to aging. There's not going to be one single pill that eliminates cancer, Alzheimer's disease, and every other disease of aging. Diseases of aging aren't caused by just one type of damage, so in the long run to make us all healthier, we're going to have to use multiple medicines targeted at the different types of damage. For example, in Alzheimer's disease we may need to both break down unwanted protein aggregates and also regulate glucose levels to really beat the disease. Cancer might need increased immune surveillance and also better DNA repair. For this reason, I think we'll see the serious benefits to healthy lifespan once we start combining multiple safe and effective therapeutics.

If you develop a drug for a rare disease, it will be very expensive. So if it also works as an anti-aging therapy, will it only be affordable to the rich?

Drug prices can always come down to match a market. Let's say our drug starts out as chronic treatment for an orphan disease. Our next trial would be to prevent Alzheimer's or early stage Parkinson's or something like this, in which you give it chronically to a large number of healthy or nearly healthy people. If it succeeds, the price point for that drug will have to drop really sharply to match the market. Something that can increase the median healthy lifespan of a population, even if it's just for a year or two years, already approaches the value of a miracle cure for cancer. Even if it's a quarter of a cure for cancer, it's still a massive deal.


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