Fight Aging!

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/

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Contents

• Three Years of Gut Microbiome Data for Flagellin Immunization and Fecal Microbiota Transplantation
• Unity Biotechnology Demonstrates Again that Localized Use of Senolytics Is Not So Great
• A Flawed Software Framing of Programmed Aging
• Modeling the Contribution of Cellular Senescence to the Tradeoff Between Cancer Risk and Aging
• Analysis of Historical Data Shows Periods of Increasing Human Maximum Life Span
• DNA Repair Can Be Improved by Suppression of the DREAM Complex
• A Glial Cell Senescence Hypothesis for Alzheimer's Disease
• Looking at the Connection Between Mitochondrial Dysfunction and Inflammation
• Senescent Cells Outside the Brain Contribute to Dysfunction in the Brain
• Triggering the STING Pathway Suppresses Cancer Metastasis
• Targeting Microglia as a Treatment for Age-Related Neurodegeneration
• Inhibiting the Ability of Cells to Resist Reprogramming Improves Transdifferentiation Therapy
• Towards An Aging Clock Based on Retinal Imaging of the Microvasculature
• Reporting on the Immune System Composition of Centenarians
• Reviewing What is Known of TDP-43 Aggregation in Neurodegeneration

Three Years of Gut Microbiome Data for Flagellin Immunization and Fecal Microbiota Transplantation
https://www.fightaging.org/archives/2023/04/three-years-of-gut-microbiome-data-for-flagellin-immunization-and-fecal-microbiota-transplantation/

I've posted in the past on a two year followup of a single-person self-experiment, a successful attempt to favorably adjust the balance of populations in the aging gut microbiome via a single treatment with flagellin immunization. This approach was intended to motivate the immune system into more aggressively destroying problematic microbes that tend to grow in number with age. As assessed using the Viome service, the intervention appeared to produce a sizable, lasting benefit to the quality of the gut microbiome in a basically healthy 50-ish individual. You can look back at those posts for the details of the protocol and further references regarding this use of flagellin.

As is the case for flagellin immunization, there is animal data to show that fecal microbiota transplantation from a young individual to an old individual rejuvenates the gut microbiome. There is a lot more of this animal data for fecal microbiota transplant, however, produced in varied species, and demonstrating that the improvement lasts for a lengthy period of time, and even results in improved health and extended life span.

Thus the same 50-ish individual mentioned above later undertook a fecal microbiota transplant, using donor material provided by a healthy, athletic 20-year-old volunteer, and further assessed the effects of this intervention on the gut microbiome. Stool samples were tested beforehand, one month afterwards, and six months afterwards. All of the measurements were again made using the Viome service. In the charts below, marks indicate that the flagellin immunization was conducted in 05/2020, and fecal microbiota transplant at the end of 08/2022. The dates marked on the horizontal axis are the dates of Viome testing.

In summary, while the flagellin intervention greatly reduced microbial diversity in the process of greatly improving other metrics, that diversity was restored by fecal microbiota transplant from a young individual. That restoration appears lasting as of the six month mark. The transplant produced small gains in some of the other metrics assessed by Viome, though not to the same degree as the flagellin immunization. That may well be because much of the potential scope for improvement was already achieved. Interestingly, neither intervention did much for Metabolic Fitness. According to Viome, half of the population falls into the 22-28 range for Metabolic Fitness (on a scale of 0 to 100!) which makes one wonder a little regarding the algorithm used in the construction of this value.

The protocol for conducting a fecal microbiota transplant at home is almost too simple to talk about, but there are a few points that are worthy of thought. The mechanics of it are straightforward. A fresh stool sample is provided by the donor, and that material is mixed with water. A few fluid ounces of the result are delivered as an enema. The recipient then lies in a suitably sloped position, abdomen higher than chest, for 30 minutes or so, in order to encourage the enema fluid to flow as deeply as possible into the intestine. Repeat this process for two to three times a few days to a week apart.

As to the points worth of thought: when fecal microbiota transplantation is conducted in the clinic as a treatment for C. difficile infection, colonic cleansing and colonoscopy equipment may be used, but more importantly, donor stool samples are screened for potentially pathogenic microbes that an older individual may respond poorly to. This screening is wise for an older recipient, as the aged immune system is far less competent than a young immune system, and that is an important factor when it comes to suppressing undesirable microbial species in the gut. What is innocuous to a young person may be much less innocuous to an old person. Rather than going through the process of finding a willing, healthy volunteer, and rolling the dice on potential issues, one can use services that will sell screened and characterized stool samples from young individuals, such as Human Microbes. This is recommended.

Unity Biotechnology Demonstrates Again that Localized Use of Senolytics Is Not So Great
https://www.fightaging.org/archives/2023/04/unity-biotechnology-demonstrates-again-that-localized-use-of-senolytics-is-not-so-great/

Most of the research relevant to the question of whether localized clearance of senescent cells can effectively treat age-related conditions has taken place in the context of osteoarthritis. While adding senescent cells to a joint is sufficient to provoke the onset of osteoarthritis, clearing senescent cells from only the joint region is not sufficient to produce significant patient benefits. The present consensus is that the senescent cells present in the rest of the body are producing a significant contribution by their signaling: those cells may be more distant, and their contributions thus more dilute, but there are a lot more of them.

UNITY Biotechnologies chose to pursue localized administration of senolytics in their initial phase 1 and phase 2 trials for both knee osteoarthritis and macular degeneration. Adopting a localized injection strategy is a time-worn approach intended to make things easier with regulators, as the much lower, localized dose means that there is a greatly reduced risk of side-effects. Unfortunately for UNITY investors, the outcome has been a demonstration, first in the knee, and now in the eye, that localized removal of senescent cells produces some benefit, but not as much as hoped, and not enough to show a clear advantage in human trials.

The conclusion adopted by the rest of the industry is that systemic, whole-body clearance of senescent cells is required to remove enough of the harmful effect of the senescence-associated secretory phenotype (SASP) on tissue function to produce meaningful gains for patients.

UNITY Shares Nearly Halved after Lead Asset Fails to Match Regeneron's Eylea

UNITY Biotechnology's lead asset, UBX1325, failed to show non-inferiority to Regeneron's anti-VEGF drug aflibercept in a Phase II wet age-related macular degeneration (wAMD) trial. This sent the biotech's shares tumbling 46% in premarket trading on Monday. The 24-week data are from the Part A portion of the proof-of-concept Envision study of UBX1325, a Bcl-xL inhibitor. The trial involved 51 patients with wAMD who received either two 10 mcg doses of UBX1325 at week zero and week four or anti-VEGF agent aflibercept 2 mg every eight weeks.

The trial used the Early Treatment Diabetic Retinopathy Study (ETDRS) to assess the therapies, which revealed an early and unexpected visual gain of 3.5 ETDRS letters with aflibercept, according to Unity. The 3.5-letter gain with aflibercept was mostly maintained for the study's duration. UBX1325 monotherapy, meanwhile, reduced letters by 0.8 from baseline.

Patients were already receiving aflibercept when they enrolled in the trial, but benefit from the therapy was not optimal, according to the press release. More than half (52%) of patients who received UBX1325 did not require anti-VEGF treatment throughout the 24 weeks of the trial, UNITY reported.

UNITY Biotechnology Announces Results from Phase 2 ENVISION Study of UBX1325 in Patients with Wet Age-Related Macular Degeneration

UNITY Biotechnology, Inc. ("UNITY"), a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced results from Part A of the Phase 2 ENVISION study of UBX1325 in patients with wet age-related macular degeneration (AMD) who were not achieving optimum benefit with their ongoing anti-VEGF therapy. UBX1325 treatment generally maintained visual acuity for 6 months (change of -0.8 ETDRS letters from baseline), with a majority of patients not requiring any anti-VEGF rescue. Patients in the every 8-week aflibercept arm had an early and unexpected gain of 3.5 letters at week 2 which was mostly maintained for the duration of the study. As a result of the strength on the control arm, the study did not meet the non-inferiority threshold compared to aflibercept through 24 weeks.

"Maintenance of visual acuity in hard-to-treat patients with active disease after withdrawal of their anti-VEGF therapy suggests that UBX1325 had an active treatment effect in wet AMD. We continue to be impressed with the durability of effect of UBX1325 in this patient population. Following a full analysis of ENVISION results, we will assess and optimize our resource allocation for future development of UBX1325. In the weeks ahead we will provide an update on Part B of the ENVISION study, and importantly, share 48-week data from the Phase 2 BEHOLD DME study. In DME, UBX1325 showed strong evidence of biologic activity and improvement in visual acuity - and, as a result, we plan to initiate a Phase 2b study in the second half of this year."

A Flawed Software Framing of Programmed Aging
https://www.fightaging.org/archives/2023/04/a-flawed-software-framing-of-programmed-aging/

The hypothesis that aging is a genetic program that is to some degree selected has always been a vocal minority view in the research community. There are just as many quite diverse theories of programmed aging as there are more mainstream evolutionary theories of aging that orbit the concept of antagonistic pleiotropy, the idea that lesser selection pressure in late life, because early reproduction means greater evolutionary fitness, allows for the evolution of mechanisms that are beneficial in youth and harmful in late life. There is even a fusion of the two sides: the hyperfunction theory of programmed aging suggests that aging is a consequence of developmental processes that fail to shut down.

One modern way of framing programmed aging is to consider the operations of cellular biochemistry derived from the genome as analogous to computer software, and aging the consequence of flaws in that software. If such software was evolved rather than designed, as some software is these days. That said, it is important to note that calling, say, the ability of a biological system to accumulate a specific form of damage and dysfunction a flaw (or a bug, or some other appropriate term for software that isn't behaving as desired) says nothing of how hard it might be to produce a better version that lacks this flaw.

It seems self-evident that at some point in the future our not entirely biological descendants, possessing some system for specifying the seed of an individual that is derived from or incorporating DNA, will be engineered to be functionally immortal. Immortal lower animals exist, such as the hydra that is essentially a steady state embryo, an ambulatory bundle of stem cells. Reconciling (a) the necessary mechanisms of constant growth, repair, and replacement to sustain an organism indefinitely with (b) the need for a central nervous system that maintains memory and state over time seems a challenging project, to say the least, however. At present it would be a major undertaking to alter one gene in the human genome while having any confidence that the outcomes are fully understood, let alone producing an entirely new functionally immortal higher species.

Thus for now it seems that the best approach to aging is based on repair. Don't try to alter the biochemistry that we have; accept its flaws, and attempt to repair the well-known forms of damage that accumulate with age as a result of those flaws. Comparatively little effort has so far been put towards building therapies capable of damage repair, while the specific desired forms of repair are quite well understood, that pursuing repair seems a much better use of time than building incremental first steps towards a distant future of an engineered, ageless genome.

Ageing as a software design flaw

Many theories of why we age have been proposed, including damaged-based and programmatic theories, with the former currently more widely accepted and studied. Most damage-based theories postulate that inefficient repair mechanisms result in singular or multiple, and often interacting, forms of damage accumulation. Although damage can be broadly defined as any change that affects function, here I refer more specifically to molecular damage hypothesized to drive ageing, such as by-products of metabolism, unwanted chemical modifications, and other types of molecular damage affecting crucial cellular components like the genome, telomeres, mitochondria, and proteins. By contrast, programmatic theories argue that ageing results from predetermined mechanisms encoded in the genome, rather than stochastic damage accumulation.

The concept of information in biology has a long history, and biological systems can be seen as highly complex information systems. Likewise, the idea that ageing could be linked to information decay or loss has been proposed, in particular in the context of the information theory of ageing. According to this theory, loss of genetic or epigenetic information with age, driven by DNA damage, is the primary cause of ageing. One hypothesis is that errors accrue in the DNA, corrupting the information in the genome and ultimately disrupting tissue homeostasis and causing ageing. More broadly, the idea that errors or damage to one or more biological types of hardware, including the DNA, accumulate and drive the process of ageing has been prevalent for decades. By hardware I encompass all elements of biological systems, including organs, tissues and the basic unit of life, the cell, and its structures (mitochondria, telomeres, proteins, DNA, and so on), most of which have at some point been hypothesized to be important in ageing.

What if, however, the processes that cause ageing are not a product of inevitable molecular damage but rather intrinsic features of the software? In this context, I define software as the genetic program, the DNA code that orchestrates how a single cell becomes an adult human being capable of reproducing, ultimately our evolutionary purpose. Herein, I present and explore the hypothesis that perhaps ageing is not a result of inevitable wear and tear or accumulated molecular damage in the hardware but rather that ageing is caused by design flaws in the software itself. I discuss manipulations of ageing and how they support this hypothesis, acknowledge exceptions, and lastly, propose areas of future study.

Modeling the Contribution of Cellular Senescence to the Tradeoff Between Cancer Risk and Aging
https://www.fightaging.org/archives/2023/04/modeling-the-contribution-of-cellular-senescence-to-the-tradeoff-between-cancer-risk-and-aging/

Researchers consider that the state of late life health in humans, and the mechanisms involved, are a balance between risk of death by cancer and risk of death by loss of tissue function. Cancer risk is increased by the activity of damaged cells, particularly stem cells, in a dysfunctional tissue environment, while loss of tissue function is accelerated by suppressing that activity. Tissue must be maintained, such as via a supply of new cells to replace losses, and cells must be active in order for that maintenance to occur.

Cellular senescence is a part of this balance of benefit and harm. Cellular senescence is a cancer suppression mechanism, halting the replication of cells at risk of becoming cancerous, as well as attracting the attention of the immune system to the local area via inflammatory signaling. Too much cellular senescence, and a lasting burden of cellular senescence when senescent cells are not efficiently destroyed by the immune system, disrupts tissue function and accelerates degenerative aging via that very same inflammatory signaling, however.

The advent of senolytic therapies to selectively destroy senescent cells will allow us to have our cake and eat it. If senescent cells are only periodically removed by treatment, then the short-term benefit of cellular senescence in suppression of immediate cancer risk resulting from cell damage will be retained, while the long-term downside of lingering senescent cells will be eliminated.

Modeling of senescent cell dynamics predicts a late-life decrease in cancer incidence

Current oncogenic theories state that tumors arise from cell lineages that sequentially accumulate (epi)mutations, progressively turning healthy cells into carcinogenic ones. While those models found some empirical support, they are little predictive of intraspecies age-specific cancer incidence and of interspecies cancer prevalence. Notably, in humans and lab rodents, a deceleration (and sometimes decline) of cancer incidence rate has been found at old ages. Additionally, dominant theoretical models of oncogenesis predict that cancer risk should increase in large and/or long-lived species, which is not supported by empirical data.

Here, we explore the hypothesis that cellular senescence could explain those incongruent empirical patterns. More precisely, we hypothesize that there is a trade-off between dying of cancer versus dying of other ageing-related causes. This trade-off between organismal mortality components would be mediated, at the cellular scale, by the accumulation of senescent cells. In this framework, damaged cells can either undergo apoptosis or enter senescence. Apoptotic cells lead to compensatory proliferation, associated with an excess risk of cancer, whereas senescent cell accumulation leads to ageing-related mortality.

To test our framework, we build a deterministic model that first describes how cells get damaged, undergo apoptosis, or enter senescence. We then translate those cellular dynamics into a compound organismal survival metric also integrating life-history traits. We address four different questions linked to our framework: can cellular senescence be adaptive, do the predictions of our model reflect epidemiological patterns observed among mammal species, what is the effect of species sizes on those answers, and what happens when senescent cells are removed? Importantly, we find that cellular senescence can optimize lifetime reproductive success. Moreover, we find that life-history traits play an important role in shaping the cellular trade-offs.

Analysis of Historical Data Shows Periods of Increasing Human Maximum Life Span
https://www.fightaging.org/archives/2023/04/analysis-of-historical-data-shows-periods-of-increasing-human-maximum-life-span/

Remaining life expectancy at 65 has increased by a year with every passing decade since at least the middle of the 20th century, an improvement that has occurred without deliberate targeting of the mechanisms of aging. To what degree is this observed trend in human life expectancy due to (a) a general slowing of aging that will carry on throughout the entire life span, and thus lengthen maximum observed life span, or (b) a more selective slowing of processes of aging that does not meaningfully impact lifespan-limiting mechanisms that operate in late life, and thus does not lengthen maximum life span?

For example, we know that supercentenarians (the tiny fraction of people who live to be age 110 and older) exhibit significant degrees of transthyretin amyloidosis, and this may be the majority cause of death in that age category. Much earlier in old age, this form of amyloidosis is present but probably not a major killer in comparison to other mechanisms of aging. It is entirely plausible that positive effects on life span resulting from past improvements in medical technology and changing lifestyle choices could have limited effects on this one specific issue, and thus would have a limited effect on maximum human lifespan.

Whether or not this is the case or is an open question, however. This is an interesting area scientific inquiry, and today's open access paper is a worthy and novel addition to the literature regarding historical trends in life expectancy, but this work is of limited relevance to efforts to extend human life. We have a list of causative mechanisms of aging to target for repair, and a biotechnology community advanced enough to undertake that work. The best approach to the treatment of aging as a medical condition is to start fixing issues and see how it goes: clearance of senescent cells, for example, is performing exceptionally well in animal models, and will hopefully see greater progress into human use in the years ahead.

Mortality postponement and compression at older ages in human cohorts

A key but unresolved issue in the study of human mortality at older ages is whether mortality is being compressed (which implies that we may be approaching a maximum limit to the length of life) or postponed (which would imply that we are not). We summarize historical mortality data in 19 currently-industrialized countries by birth cohort using a variant of the Gompertz mortality law, and find that it fits cohort mortality data extremely well. Using this law, we identify the youngest age at which individuals in each cohort reach an assumed mortality plateau, which we call the Gompertzian Maximum Age (GMA). We find that over much of the period covered by our data, there was no increase in the GMA. Historical improvements in life expectancy were therefore largely the result of mortality compression. We demonstrate, however, that there have been episodes where the GMA increased. The presence of these episodes of mortality postponement suggests that the maximum length of a human life is not, in fact, fixed.

The first episode of mortality postponement that we identify occurred for cohorts born in the early part of the second half of the 19th century, and was more pronounced for females than for males. Over this period, the GMA increased by around 5 years. We can only speculate as to the causes of this increase, but as the first of these cohorts reached age 50 just after 1900 and the last reached age 100 in 1980, this may be related to a first wave of improvements in public health and medical technology. We identify a second, and much more significant, episode of mortality postponement, which is affecting cohorts born between 1910 and 1950 (so those currently aged between 70 and 110). We estimate that the GMA for these cohorts may increase by as much as 10 years, and remaining life expectancy at age 50 by as much as 8 years, depending on the country.

The timing of these episodes of mortality postponement explain why longevity records have been so slow to increase in recent years - cohorts old enough to have broken longevity records were too old to experience the current bout of postponement - and identifies significant potential for longevity records to rise by the year 2060 as younger cohorts, who did experience it, reach advanced old age. Our results on the division of changes in remaining life expectancy at age 50 across cohorts between compression and postponement are robust to our modelling choices. Likewise, our conclusion that longevity records will likely be broken in the coming decades is also robust to a wide range of possible assumptions. But our predictions of precisely by how much these records will rise, and when, depend on our modelling assumptions, in particular on the maximum mortality rate we assume.

We emphasise further that cohorts born before 1950 will only have the potential to break existing longevity records if policy choices continue to support the health and welfare of the elderly, and the political, environmental and economic environment remains stable. The emergence of Covid-19 and its outsize effect on the mortality of the elderly provides a salutary warning that none of this is certain. If, however, the GMA does increase as the current mortality experience of incomplete cohorts suggests is likely, the implications for human societies, national economies, and individual lives will be profound.

DNA Repair Can Be Improved by Suppression of the DREAM Complex
https://www.fightaging.org/archives/2023/04/dna-repair-can-be-improved-by-suppression-of-the-dream-complex/

Researchers here describe a mechanism that appears to reduce DNA repair efficiency, and which can be suppressed to improve DNA repair. This is interesting, to say the least. It might be a path to determining just how much of a contribution to the pace of aging is produced by efficiency of DNA repair. The interaction between this and the finding that repeated cycles of double strand break repair induce epigenetic changes characteristic of aging is also an intriguing question. Mammalian studies sooner rather than later are called for.

The DNA-repair capacity in somatic cells is limited compared with that in germ cells. It has remained unknown whether not only lesion-type-specific, but overall repair capacities could be improved. Here we show that the DREAM repressor complex, formed by the Dp/Retinoblastoma(Rb)-like/E2F and the MuvB subcomplexes, curbs the DNA-repair capacities in somatic tissues of Caenorhabditis elegans. Mutations in the DREAM complex induce germline-like expression patterns of multiple mechanisms of DNA repair.

Consequently, DREAM mutants confer resistance to a wide range of DNA-damage types during development and aging. Similarly, inhibition of the DREAM complex in human cells boosts DNA-repair gene expression and resistance to distinct DNA-damage types. DREAM inhibition leads to decreased DNA damage and prevents photoreceptor loss in progeroid Ercc1-/- mice. We show that the DREAM complex transcriptionally represses essentially all DNA-repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA-repair capacities.

A Glial Cell Senescence Hypothesis for Alzheimer's Disease
https://www.fightaging.org/archives/2023/04/a-glial-cell-senescence-hypothesis-for-alzheimers-disease/

Senescent cells accumulate with age throughout the body, and evidence is increasingly supportive of a role for cellular senescence in the development of Alzheimer's disease. This is particularly the case for senescent supporting cells in the brain, such as microglia and astrocytes, but the inflammatory signaling produced by senescent cells elsewhere in the body may well be just as influential on dysfunction in brain tissue. Given the capacity to clear senescent cells, and at least one recently launched trial of senolytic therapies to clear senescent cells in Alzheimer's patients, we should see some progress in the years ahead, towards a better understanding of the relevance of cellular senescence to age-related neurodegeneration.

Alzheimer's disease (AD) predominantly occurs as a late onset (LOAD) form involving neurodegeneration and cognitive decline with progressive memory loss. Risk factors that include aging promote accumulation of AD pathologies, such as amyloid-beta and tau aggregates, as well as inflammation and oxidative stress. Homeostatic glial cell states regulate and suppress pathology buildup; inflammatory states exacerbate pathology by releasing pro-inflammatory cytokines. Multiple stresses likely induce glial senescence, which could decrease supportive functions and reinforce inflammation.

In this perspective, we hypothesize that aging first drives AD pathology burden, whereafter AD pathology putatively induces glial senescence in LOAD. We hypothesize that increasing glial senescence, particularly local senescent microglia accumulation, sustains and drives perpetuating buildup and spread of AD pathologies, glial aging, and further senescence. We predict that increasing glial senescence, particularly local senescent microglia accumulation, also transitions individuals from healthy cognition into mild cognitive impairment and LOAD diagnosis. These pathophysiological underpinnings may centrally contribute to LOAD onset, but require further mechanistic investigation.

Looking at the Connection Between Mitochondrial Dysfunction and Inflammation
https://www.fightaging.org/archives/2023/04/looking-at-the-connection-between-mitochondrial-dysfunction-and-inflammation/

Every cell contains hundreds of mitochondria, each with its own genome, mitochondrial DNA separate from that of the cell nucleus. The primary role of mitochondria is to generate chemical energy store molecules, adenosine triphosphate (ATP), used to power cell activities. Mitochondrial dysfunction with aging isn't just a loss of ATP generation and production of a harmful amount of reactive oxygen species, however. It can also be connected with chronic inflammation, as mislocalization of mitochondrial DNA can trigger sensors of the innate immune system to provide inflammatory signaling. Mitochondria are the descendants of ancient symbiotic bacteria, and there is a certain degree of overlap in the evolved mechanisms that detect the presence of bacteria and those that detect cellular damage and dysfunction. This is all the more reason for a greater focus on the development of ways to reverse the mitochondrial dysfunction observed in older individuals.

In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin.

In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.

Senescent Cells Outside the Brain Contribute to Dysfunction in the Brain
https://www.fightaging.org/archives/2023/04/senescent-cells-outside-the-brain-contribute-to-dysfunction-in-the-brain/

While rising numbers of senescent cells in the brain, particularly microglia, are thought to contribute to age-related neurodegeneration, researchers here report on data that strongly suggests senescent cells in the rest of the body collectively produce a larger harmful effect. Two senolytic treatments, one that can readily access the brain, and one that cannot, produce quite similar outcomes in an animal study of neurodegeneration. We might add this data to other indications that senescent cell pro-inflammatory signaling is a body-wide phenomenon, and thus removing senescent cells locally will likely be insufficient to help patients.

We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood-brain barrier (BBB) integrity, and prevented the age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function associated with impaired cognition.

Compared to older controls, senolytic treatments decreased transcription of dentate gyrus genes linked to oxidative stress and immune response, and increased the expression of synaptic genes. However, D + Q had a greater effect on brain transcription categories associated with cellular senescence, decreasing expression of genes linked to apoptosis, regulation of apoptosis, and microglial activation that were not significant for ABT-263 treatment. Dissimilarities associated with brain transcription indicate divergence in central mechanisms, possibly due to differential brain access. Previous work indicates that dasatinib enters the central nervous system to clear senescent cells. In contrast, ABT-263 does not cross the BBB, which may explain differential effects.

Triggering the STING Pathway Suppresses Cancer Metastasis
https://www.fightaging.org/archives/2023/04/triggering-the-sting-pathway-suppresses-cancer-metastasis/

Most cancers would become manageable if metastasis could be eliminated. A robust way to fully suppress metastasis across all forms of cancer would not be a cure in and of itself, but it would greatly reduce mortality and allow cancers to be managed or eliminated more readily, and with less trauma for the patient. On the way to a hypothetical end to metastasis, researchers are making inroads towards approaches that may at least reduce metastasis to some degree. These approaches often, as here, involve ways to enlist the immune system to more aggressively target and destroy metastatic cells before they can build a new tumor.

Even when a primary tumor is successfully treated, cells that have broken away from the tumor often linger in the body in a dormant state that allows them to evade detection by the immune system for years at a time. Then, after the dormant cells have developed new traits to help them survive, they can wake up and start their runaway growth again. "These tumor cells are not in a supportive environment at the beginning. So they have to adapt and develop their own self-supporting niche until they're ready, eventually, to wake up and start a fast-growing metastasis. The interaction with the person's immune system is very important to this process."

Using mouse models of early-stage metastasis from lung cancer, the research team conducted a genetic screen to look at the activity of genes in the tumor cells that are important for interactions with the host's immune system. That's how they identified the STING pathway - an acronym for stimulator of interferon genes - as a suppressor of metastatic outbreaks. Importantly, the researchers found that STING expression changes across different stages of metastasis. In the dormant stage, STING activity is low - and the dormant cells excel at hiding out from immune defenders. Moving out of the dormant stage and into an awakened, proliferative stage, the metastatic cells start to have increased STING activity. This makes them more vulnerable to attack by the immune system. But cells that survive this bottleneck to generate larger clusters, called macrometastastes, again show reduced STING levels, which makes them more resistant to the immune system.

Using STING activators in conjunction with that window of increased STING activity in the reawakened cancer cells could be an opportunity to help the body's immune defenders destroy them. Indeed, when scientists artificially increased STING signaling in those aggressive metastatic cells, they attracted more immune defenders like natural killer cells and T cells, which swooped in to kill them off. And when the scientists activated STING in mice lacking key immune cells, metastasis still developed - pointing to a critical role for STING in recruiting the immune cells to attack the cancer cells.

Targeting Microglia as a Treatment for Age-Related Neurodegeneration
https://www.fightaging.org/archives/2023/04/targeting-microglia-as-a-treatment-for-age-related-neurodegeneration/

Researchers here discuss some of the details involved in present efforts to adjust the behavior of inflammatory microglia in the aging brain. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. A sizable body of evidence implicates the ever more inflammatory activities of microglia in the onset and progression of neurodegenerative conditions. Innate immune cells react in this way to molecular signs of damage and cell stress produced by other aspects of aging, but when a state of inflammatory signaling persists for the long-term, it becomes harmful in and of itself, altering cell behavior for the worse throughout tissue, and producing dysfunction.

As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits. Increases in microglial inflammatory activity are thought to contribute to age-related declines in cognitive functions and to transitions toward mild cognitive impairment (MCI) and Alzheimer's disease (AD). As microglia possess receptors for communicating with the CNS environment, pharmacological therapies targeting these pathways hold potential for promoting homeostatic microglial functions within the aging CNS.

Preclinical and early phase clinical trials investigating the therapeutic effects of pharmacological agents acting on microglia, including reactive oxygen species, TREM2, fractalkine signaling, the complement cascade, and the NLRP3 inflammasome, are currently underway; however, important questions remain unanswered. Current challenges include target selectivity, as many of the signaling pathways are expressed in other cell types. Furthermore, microglia are a heterogenous cell population with transcriptomic, proteomic, and microscopy studies revealing distinct microglial states, whose activities and abundance shift across the lifespan. For example, homeostatic microglia can transform into pathological states characterized by markers of oxidative stress.

Selective pharmacological targeting aimed at limiting transitions to pathological states or promoting homeostatic or protective states, could help to avoid potentially harmful off-target effects on beneficial states or other cell types. In this mini-review we cover current microglial pathways of interest for the prevention and treatment of age-related cognitive decline and CNS disorders of aging focusing on MCI and AD. We also discuss the heterogeneity of microglia described in these conditions and how pharmacological agents could target specific microglial states.

Inhibiting the Ability of Cells to Resist Reprogramming Improves Transdifferentiation Therapy
https://www.fightaging.org/archives/2023/04/inhibiting-the-ability-of-cells-to-resist-reprogramming-improves-transdifferentiation-therapy/

Researchers here discuss an interesting approach to transdifferentiation as a basis for therapy. In transdifferention, a cell of one type is reprogrammed to become another type directly, without passing through an intermediary stage of dedifferentiation to pluripotency. There has long been interest in directly converting scar tissue cells into heart muscle cells following a heart attack or similar injury, as animal studies have been promising. How do cells hold on to their state and resist a change of cell identity, however? If the mechanisms holding cell state firm can be identified and inhibited, then cells can be more readily changed into other cell types. That is demonstrated here in heart tissue, a novel approach to the challenge of enhancing regeneration in this normally poorly regenerative organ.

Defining the mechanisms safeguarding cell fate identity in differentiated cells is crucial to improve 1) our understanding of how differentiation is maintained in healthy tissues or altered in a disease state, and 2) our ability to use cell fate reprogramming for regenerative purposes. Here, using a genome-wide transcription factor screen followed by validation steps in a variety of reprogramming assays (cardiac, neural and iPSC in fibroblasts and endothelial cells), we identified a set of four transcription factors (ATF7IP, JUNB, SP7, and ZNF207, collective AJSZ) that robustly opposes cell fate reprogramming in both lineage and cell type independent manners.

Mechanistically, our approach revealed that AJSZ oppose cell fate reprogramming by 1) maintaining chromatin enriched for reprogramming transcription factor motifs in a closed state and 2) downregulating genes required for reprogramming. Finally, knockdown of AJSZ in combination with overexpression of cardiac reprogramming factors Mef2c, Gata4, and Tbx5, collectively MGT, significantly reduced scar size and improved heart function by 50%, by reprogramming fibroblasts into cardiomyocytes, as compared to MGT alone post-myocardial infarction.

Collectively, our study suggests that inhibition of barrier to reprogramming mechanisms represents a promising therapeutic avenue to improve adult organ function post-injury.

Towards An Aging Clock Based on Retinal Imaging of the Microvasculature
https://www.fightaging.org/archives/2023/04/towards-an-aging-clock-based-on-retinal-imaging-of-the-microvasculature/

Blood vessel density declines with age, alongside other detrimental changes in the microvasculature, such as small areas of tissue damage following microbleeds. All of this can be readily imaged in the retina, and retinal imaging is already in widespread use in clinical practices. Thus it is interesting to see progress towards an aging clock that uses this aspect of degenerative aging as a marker. A number of potential therapeutic strategies may meaningfully increase angiogenesis and thus microvascular density in later life, such as increased circulating VEGF via gene therapy, or use of existing FDA-approved CLCX12 agonists, all of which have yet to be robustly assessed as better or worse than the effects of, say, six months of a structured exercise program. A good, accessible way to measure results will hopefully speed up progress here.

The blood vessel-rich tissue in the retina, can be used to track human aging in an aging clock called eyeAge, in a way that is noninvasive, less expensive and more accurate than other aging clocks that are currently available. A growing body of evidence suggests that the microvasculature in the retina might be a reliable indicator of the overall health of the body's circulatory system and the brain. Changes in the eye accompany aging and many age-related diseases including age-related macular degeneration (AMD), diabetic retinopathy, and Parkinson's and Alzheimer's disease. Ophthalmologists can often detect early symptoms of AIDS, chronic high blood pressure and certain tumors in the eyes, a utility that is not surprising given that any subtle changes in the vascular system first appear in the smallest blood vessels, and capillaries in the retina are among the smallest in the body.

But subtle changes in these small blood vessels often go undetected by even the most sophisticated instruments, necessitating the use of deep learning, an effort spearheaded by Google Research. Researchers from Google and elsewhere developed models to predict diabetic retinopathy from retinal images and have gone on to use retinal images to identify at least 39 eye diseases including glaucoma, diabetic retinopathy, and AMD, as well as non-eye diseases such as chronic kidney disease and cardiovascular disease. Google researchers trained and tuned the model for eyeAge using their well-studied EyePACS data set which involves more than 100,00 patients and applied it to patients from the UK Biobank, which involved more than 64,000 patients.

"This type of imaging could be really valuable in tracking the efficacy of interventions aimed at slowing the aging process. The results suggest that potentially, in less than one year we should be able to determine the trajectory of aging with 71% accuracy by noting discernable changes in the eyes of those being treated, providing an actionable evaluation of geroprotective therapeutics. Our study emphasizes the value of longitudinal data for analyzing accurate aging trajectories. Through EyePACS longitudinal dataset involving multiple scans from individual people over time our results show a more accurate positive prediction ratio for two consecutive visits of individual rather than random, time-matched individuals."

Reporting on the Immune System Composition of Centenarians
https://www.fightaging.org/archives/2023/04/reporting-on-the-immune-system-composition-of-centenarians/

Centenarians exhibit some different immune systems characteristics when compared against the general population in earlier old age. Whether this will produce any meaningful degree of protection is an open question. Even if these differences are protective, one should expect that biochemical characteristics that are found to a greater degree in centenarians will only slightly improve the small odds of living to be this old in the context of the medical technology and lifestyle choices of the last century. It doesn't take much of a change, say 1.25% survival odds rather than 1% survival odds, to see a lot more of that mechanism operating in the living population very old people, when compared to the population at large. That doesn't make the underlying mechanism a desirable basis for an enhancement therapy - it is achieving far too little to be worth the time and effort.

Using a multi-modal, single cell approach, we generated cell composition and transcriptional profiles from the peripheral blood mononuclear cells (PBMCs) of 7 centenarians using CITE-seq. We integrated this novel data set with publicly available single cell RNA-seq datasets of aging and longevity across the human lifespan to characterize cell type composition and gene expression profiles unique to centenarians. The peripheral blood immune cell repertoire of individuals is known to change with age. Previous transcriptional studies have shown decreases in lymphocytes and increases in myeloid cells with age, which we also observed in the peripheral blood of centenarians. However, in addition to these common changes across aging, our analysis identified patterns of immune cell profiles and compositional alterations that are unique to centenarians.

We observed expected shifts in the composition of centenarians' PBMCs from non-cytotoxic (e.g., naive CD4+ T cells and memory CD4+ T cells) to cytotoxic lymphocytes (e.g., cytotoxic CD4+ T cells) that have been observed previously in studies of human longevity. Similarly, the decrease of naive B cells with aging and longevity has also been reported previously. However, we also discovered novel compositional patterns of extreme old age including aging-related changes (e.g. a significant increase of CD14+ monocytes in older age that continues in the centenarian group), centenarian-specific changes (e.g. myeloid dendritic cells and plasmacytoid dendritic cells display no significant change among the three younger age groups but a unique, significant decrease occurs in extreme longevity), and aging-specific changes independent of extreme longevity (e.g. a significant increase of CD16+ monocytes in older age that then decreases in the centenarian age group).

The extent to which these unique patterns in centenarians are the drivers of extreme longevity or just the consequence of having reached an extreme old age remains an open question, since not everything we see in centenarians is necessarily important to reach extreme old ages. Additional data are needed to understand the effect of these patterns on human longevity. Overall, these findings display age-related changes in composition and transcription in both lymphocyte and myeloid cell types that collectively reflect immunocompetent profiles that may in part account for centenarians' ability to reach extreme ages.

Reviewing What is Known of TDP-43 Aggregation in Neurodegeneration
https://www.fightaging.org/archives/2023/04/reviewing-what-is-known-of-tdp-43-aggregation-in-neurodegeneration/

TDP-43 is one of the more recently discovered protein aggregates involved in neurodegenerative conditions. A few proteins in the body are capable of misfolding or otherwise becoming altered in ways that encourage other molecules of the same protein to do the same. Toxicity results, and it can spread as these altered proteins move from cell to cell. The condition most clearly associated with TDP-43 pathology is amyotrophic lateral sclerosis (ALS), but it appears to be involved in other forms of neurodegenerative disease as well. Researchers have made inroads into understanding how these aggregates form and disrupt normal cellular operations, but as yet little progress has been made towards development of a viable approach to therapy.

TAR DNA binding protein 43 kDa (TDP-43) plays an important role in several essential cell functions. However, TDP-43 dysfunction has been implicated in the development of various brain diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Recent investigations into the individual components of TDP-43 pathology show how broader TDP-43 dysfunction may precede these disease end states, and therefore could help to explain why TDP-43 dysfunction continues to be implicated in a rapidly expanding category of neurodegenerative diseases.

TDP-43 pathology is usually characterized by insoluble, hyperphosphorylated and ubiquinated aggregates of TDP-43 in the cytoplasm, nucleus, and cell processes of neurons and glia. Mislocalization of TDP-43 within cellular compartments is also characteristic of the pathology. Normally TDP-43 is tightly auto-regulated and is almost entirely located in the nucleus. Consequently, depletion of TDP-43 in the nucleus, in association with abnormally high levels in the cytoplasm, is considered to be pathological. Indeed, TDP-43 mislocalization alone appears capable of causing mRNA instability, impaired gene regulation, mitochondrial dysfunction, impaired protein turnover, among other issues. However, the underlying causes of TDP-43 mislocalization and aggregation remain unclear.

The literature reviewed in this article suggests that dysregulation of TDP-43 initiated by some environmental and/or genetic insults can lead to a snowballing dysfunction across the cell, involving impaired gene expression, mRNA stability, as well as the function and coordination of those pathways directly regulated by TDP-43. Furthermore, the hallmarks of TDP-43 pathology, such as hyperphosphorylation and insoluble cytoplasmic accumulation of the protein may actually be artifacts of an upstream impairment in TDP-43's normal function.