Fight Aging!

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Contents

• Considering the Longevity of Elephants
• Reviewing What is Known of the Longevity Gene INDY
• Mitrix Bio Works on the Production of Mitochondria for Transplantation
• Doubling Down on the Failure of Amyloid-β Clearance
• Efficient Epigenetic Clocks May Not Be Useful Epigenetic Clocks
• Suggesting that 40% of Dementia is the Result of Lifestyle and Environment
• Aubrey de Grey on Progress in SENS Rejuvenation Research
• An Omics View of the Inflammation of Aging
• Inflammatory Pathways Triggered by the Aging Gut Microbiome Converge on NF-κB
• PEDF in the Retina, an Example of the Slow Pace of Progress
• Mosaic Loss of Y Chromosome Provokes Macrophage Dysfunction and Inflammation
• Inundated with an Ideology of Death-Acceptance
• A Lipid Based Aging Clock
• Detecting Alzheimer's Disease Seventeen Years in Advance
• Autophagy as a Therapeutic Target

Considering the Longevity of Elephants
https://www.fightaging.org/archives/2022/07/considering-the-longevity-of-elephants/

Much of the recent research into the longevity of large mammals such as elephants has focused on Peto's paradox. If the odds of cancer are based on the number of cells in the body, all of which undergo stochastic and potentially cancerous mutations at some rate, then how is it that large mammals, with many times more cells in their body, do not exhibit a correspondingly larger risk of cancer? The answer being that for larger mammals to evolve at all, their cancer risk must be managed downward by changes in cellular biochemistry that reduce mutation rate or more efficiently destroy potentially cancerous cells. In elephants this appears to be achieved, in large part at least, by the 20-fold duplication of TP53, a cancer suppression gene.

There is a lot more to think about when it comes to the longevity of elephants, however, and today's open access review paper is an interesting read on this topic. For example, the unusual biology of hormones in male elephants, combined with the mating behavior of elephants in general, leads to greater reproductive success later in life, which likely puts selection pressure on greater longevity. Something much like this, or analogous situations such as the Grandmother hypothesis in humans, in which intelligence and culture allows older individuals to materially contribute to the reproductive success of their grandchildren, must exist in order to drive the evolution of increased longevity in a species.

Aging: What We Can Learn From Elephants

Elephants are large-brained, social mammals with a long lifespan. Studies of elephants can provide insight into the aging process, which may be relevant to understanding diseases that affect elderly humans because of their shared characteristics that have arisen through independent evolution. Elephants become sexually mature at 12 to 14 years of age and are known to live into, and past, their 7th decade of life. Because of their relatively long lifespans, elephants may have evolved mechanisms to counter age-associated morbidities, such as cancer and cognitive decline. Elephants rely heavily on their memory, and engage in multiple levels of competitive and collaborative relationships because they live in a fission-fusion system in which groups change membership frequently. Female matrilineal relatives and dependent offspring form tight family units led by an older-aged matriarch, who serves as the primary repository for social and ecological knowledge in the herd. Similar to humans, elephants demonstrate a dependence on social bonds, memory, and cognition to navigate their environment, behaviors that might be associated with specializations of brain anatomy.

Males have a unique combination of behavioral and physiologic traits that reflect the intense pressure to compete for access to estrous females. In general, females are in estrous for only 3-6 days every 3-9 years. Males grow throughout much, or perhaps all, of their lifespan, in terms of stature, as well as body and tusk weight. Males experience musth, unique to elephants, which is characterized by bouts of elevated testosterone and aggression, and heightened sexual activity. Females prefer larger males and those in musth, which may explain why paternity success steadily increases in males from the mid-20s until it peaks around early 50s, after which, it is comparable to a male in his early 40s. This observation suggests male elephants may undergo sexual selection for longevity.

One mechanism allowing elephants to reach longer lifespans may be their multiple copies of the tumor suppressor gene TP53, colloquially known as the "guardian of the genome." Humans have one copy of TP53, whereas savanna, forest, and Asian elephants are estimated to have 19-23, 21-24, and 19-22 TP53 copies, respectively. This is compared to estimates of 19-28, and 22-25 TP53 copies in the extinct woolly mammoth and straight-tusked elephant, respectively. Of the multiple elephant TP53 genes, only one appears to have a comparable gene structure to other mammals, while the other copies appear to be retrogenes, as they lack true introns. Retrogenes can have functional biological roles. Indeed, genetic variation at some elephant TP53 retrogenes is conserved across all three extant elephant species, providing evidence of the functionality of at least some TP53 retrogenes. As reported recently, TP53 is activated in response to cellular stresses in addition to DNA damage. Thus, these multiple copies may have various effects in response to cell stress. Elephants appear to have an enhanced apoptotic response to DNA damage owing to their extensive number of TP53 retrogenes and, as a result, develop cancer at lower rates than expected for their body size and lifespan.

Reviewing What is Known of the Longevity Gene INDY
https://www.fightaging.org/archives/2022/07/reviewing-what-is-known-of-the-longevity-gene-indy/

INDY was one of the earlier longevity-related genes to be robustly identified, a discovery made 20 years ago now. Much of the exploratory work on INDY was carried out in flies, though more than enough time has now passed for mouse data to have also emerged. The authors of today's review paper characterize the benefits resulting from a reduced expression of INDY as a calorie restriction mimetic effect, more or less. That is a fair enough shorthand for any approach that improves cellular maintenance processes in a way that modestly slows the aging process, resisting the accumulation of damage, dysfunctional cells, and chronic inflammation.

Most of the ways known to slow aging in short-lived species are quite similar, viewed from the high level. Given that these species exhibit a sizable plasticity of life span in response to environmental circumstances, achieved via upregulation of stress response mechanisms triggered by heat, cold, toxins, and low nutrient availability, most of what is discovered by any unbiased search are ways to trigger that same upregulation of stress response mechanisms. That has indeed been the case, with inhibition of INDY expression as one such approach. Unfortunately, this category of interventions just isn't as effective at extending life in longer-lived species, as demonstrated by the fact that calorie restriction itself adds only a few years to human life span at most, quite unlike the ~40% life extension observed in mice.

Still, calorie restriction does improve health in humans. It seems likely that out of this large range of ways to improve cellular maintenance, a fair number of drugs, like mTOR inhibitors, will emerge to produce modest gains in human patients. Likely very modest, an acceptable exchange for a low cost drug from the patient's perspective, but a grand waste of time and effort that should have gone elsewhere from the perspective of the billions spent on the drug development process in its later stages.

INDY - From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans

I'm Not Dead Yet (Indy) is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity, and disease. Reduction of Indy gene activity in flies, and its homologs in worms, modulates metabolism and extends longevity. The metabolic changes are similar to what is obtained with caloric restriction (dietary restriction). Similar effects on metabolism have been observed in mice and rats.

As a citrate transporter, INDY regulates cytoplasmic citrate levels. Indy flies heterozygous for a P-element insertion have increased spontaneous physical activity, increased fecundity, reduced insulin signaling, increased mitochondrial biogenesis, preserved intestinal stem cell homeostasis, lower lipid levels, and increased stress resistance. Mammalian Indy knockout (mIndy-KO) mice have higher sensitivity to insulin signaling, lower blood pressure and heart rate, preserved memory and are protected from the negative effects of a high-fat diet and some of the negative effects of aging. Reducing mIndy expression in human hepatocarcinoma cells has recently been shown to inhibit cell proliferation. Reduced Indy expression in the fly intestine affects intestinal stem cell proliferation, and has recently been shown to also inhibit germ cell proliferation in males with delayed sperm maturation and decreased spermatocyte numbers.

These results highlight a new connection between energy metabolism and cell proliferation. The overall picture in a variety of species points to a conserved role of INDY for metabolism and health. This is illustrated by an association of high mIndy gene expression with non-alcoholic fatty liver disease in obese humans. mIndy (mSLC13A5) coding region mutations (e.g., loss-of-function) are also associated with adverse effects in humans, such as autosomal recessive early infantile epileptic encephalopathy and Kohlschütter-Tönz syndrome. The recent findings illustrate the importance of mIndy gene for human health and disease. Furthermore, recent work on small-molecule regulators of INDY highlights the promise of INDY-based treatments for ameliorating disease and promoting healthy aging.

Mitrix Bio Works on the Production of Mitochondria for Transplantation
https://www.fightaging.org/archives/2022/07/mitrix-bio-works-on-the-production-of-mitochondria-for-transplantation/

One of the more practical near term approaches to address the age-related decline of mitochondrial function is transplantation of functional mitochondria. As an approach, it bypasses all of the remaining unknowns relating to the biochemistry of mitochondrial aging. Cells will take up whole mitochondria and make use of them, and early studies suggest that providing new mitochondria can improve tissue function when native mitochondria are impaired. It is likely that this improvement will last for only a limited time, as the same processes that degrade the function of mitochondria, such as a lack of effective mitophagy, will still operate on the new arrivals. If that limited time is a few months to a few years, that will nonetheless gives tissues a chance to restore themselves to some degree - and the therapy can always be repeated.

The major focus of the few companies presently working towards this goal of mitochondrial transplantation is the development of practical methods of production of mitochondria. Ultimately, therapies for aging humans that replace mitochondria throughout the body will require enormous numbers of these organelles, and thus the development of a cost-effective means of manufacture at scale. Even producing enough mitochondria for demonstrations in mice proved to be an initial hurdle. It is interesting to see reports along the way in this process of development, such as the materials provided by Mitrix Bio, noted here. Academic papers will be forthcoming, it seems, to describe the details.

Bioreactor-Grown Mitochondria for Potential Anti-Aging

Mitrix Bio announced early results of an 18-month project in which a series of mitochondrial transplants were performed in animal studies of brain, eye, liver, immune system, and skin tissues. In these tests, "young" highly functional mitochondria are grown in prototype bioreactors and transfused into the bloodstream. Cells absorb them to help supplement old, dysfunctional mitochondria and reverse energetic decline. These tests showed apparent age reversal in multiple endpoints in animal disease models in vivo and human cells in vitro. The results indicate potential future therapies for diseases such as Alzheimer's, macular degeneration, cardiovascular disease, frailty, and immunosenescence. Experiments not only point toward specific diseases but suggest anti-aging effects on test animals' strength, cognition, and appearance. A series of peer-reviewed papers will be released in coming months.

For the past decade, researchers have been testing exogenous mitochondrial transplants. But these tests have been confined mainly to rare pediatric diseases and surgery, not the larger world of adult diseases and longevity, due to scarce supplies of donor mitochondria. Just as liver or kidney organ transplants are limited by the availability of donors, mitochondrial "organelle transplants" are limited by scarce supplies of donor mitochondria. The Mitrix Bio project was launched to overcome this limitation for adult diseases. In the Mitrix process, the first step is to grow mitochondria in prototype bioreactors. Next, those mitochondria are given a special coating to protect against immune reactions along with molecular receptors to target specific tissue types. These coated mitochondria are infused into the body, where they travel to desired tissues and take up residence in cells.

"As people age, their tissues experience chronic energy depletion - there's not enough energy for cells to function, DNA becomes damaged, and stem cells lose their stemness. Our goal with mitochondrial transplant is to raise the energetics of the entire system so it's ready for other types of longevity treatments. All things considered, having improved bioenergetics trumps many of the negative impacts of aging. Even if improvement from mitochondrial transplant is indirect, it buys time, and that is what longevity is all about."

Doubling Down on the Failure of Amyloid-β Clearance
https://www.fightaging.org/archives/2022/07/doubling-down-on-the-failure-of-amyloid-%ce%b2-clearance/

After decades of work, researchers have finally achieved therapies that can effectively clear amyloid-β aggregates from the brains of patients with Alzheimer's disease. Unfortunately clinical trials have shown no robust benefit to patients as a result. As illustrated by today's open access paper, a sizable contingent in the research community feel that the evidence for amyloid-β aggregation to be the root of the condition remains convincing. Failure means, in their eyes, that the challenge is more difficult than hoped, and the answer should be an increased effort to run longer clinical trials, find more and better anti-amyloid therapies, and in general an increased investment in and focus on clearance of amyloid-β.

Meanwhile, many other groups have their own viewpoints, some of which are gathering a sizable body of evidence in support of different interpretations of the core amyloid cascade hypothesis of Alzheimer's disease. No-one disputes that amyoid-β aggregation is associated with the condition and harmful in animal models, but why it is there, which form of amyloid-β or which of the surrounding biochemistry should be the target, or whether amyloid-β is irrelevant to later stages of the condition, and whether amyloid-β is a side-effect of other, more important pathological mechanisms, such as sustained inflammation of brain tissue or persistent viral infection - these are all ongoing debates that have given rise to significant research programs, clinical trials, and potential therapeutics. Many of these hypotheses and the approaches that arise from them will turn out to be wrong. That list may well include the currently dominant approach to amyloid-β clearance.

If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?

Alzheimer's disease (AD) is a major threat to our aging society and will be even more so in the future as life expectancy rises. Scientists from many different disciplines have worked intensively over four decades to try to identify the triggers of the disease and, based on these findings, to develop therapeutic strategies. However, although many clinical trials using approaches based on seemingly well-identified targets have been conducted, none of them seems to have reached its final goal: to substantially slow cognitive decline. This dispiriting news has led some to conclude that decades of intense research have failed because scientists wasted their time focusing on the wrong mechanism. But is this really true? Do we indeed have no idea what triggers AD? Were all clinical trials a failure? In other words, did we simply lose valuable time by working on the wrong targets, and are there mysterious "alternative pathways" that scientists have entirely missed so far?

For decades, scientists have focused their research on a presumably stereotyped neuropathology, namely amyloid plaques and neurofibrillary tangles, both of which are found in all patients with AD. Amyloid plaques are composed of abnormal aggregated forms of the amyloid β-proteins (Aβ) that are generated normally by enzymatic cleavage from the amyloid precursor protein (APP). Amyloid plaques are extracellular, whereas neurofibrillary tangles, composed of aggregated tau proteins, occur within neurons. How are these defining lesions connected, and what triggers the pathology initially? Based on overwhelming genetic evidence, Aβ accumulation and its aggregation into amyloid plaques is capable of initiating the disease and is therefore often placed at the top of a theoretical cascade of events which, via multiple steps, leads to widespread neuronal dysfunction and death. This rather linear view of molecular events has been challenged by the proposed "cellular phase" of AD which, instead of the long-pursued neurocentric view, brings the virtually simultaneous interplay of different types of brain cells, and not just neurons, into focus. As a consequence, alternative pathways, some of which may be independent of Aβ accrual, might also trigger the disease. In this sense, AD may be thought of as a syndrome that has many different causes. But did we really miss the main pathogenic triggers and need to completely reorient AD research?

Aβ dyshomeostasis is an early, invariant, and necessary feature of AD pathogenesis. Then why has only one anti-amyloid agent achieved regulatory approval, and even then, under highly controversial circumstances? The most plausible explanation that emerges from available knowledge is that translating the robust preclinical and biomarker science of Aβ pathobiology into clear-cut clinical benefit has been logistically difficult and fraught with missteps. In our view, anti-amyloid trials have often included inadequate compounds, less than ideal patient selection, initiation of treatment too late in the biological process, and faulty trial execution, including premature trial termination and the expectation that slowing this chronic disease can be accomplished in just 12 to 18 months. The seemingly improved execution of the current Phase III antibody clinical trials (lecanemab, donanemab, and gantenerumab) suggests that we may soon obtain more convincing evidence that sustained amyloid lowering leads to decreased pathological tau, less neurodegeneration, and the blunting of cognitive and functional decline. It would therefore be highly unwise to slow or abandon our efforts to confirm anti-Aβ therapeutic candidates, particularly since alternative, albeit highly attractive, targets (such as tau, ApoE4, and microglial modulation) are well behind Aβ lowering in the quest to lessen the disease course for patients.

If genetic, biochemical, animal modeling, fluid biomarker, and imaging studies all support Aβ as a rational target, and anti-Aβ immunotherapy reduces markers of neurodegeneration and provides some cognitive benefit, what can bring us to full success? It will be quantitative preclinical confirmation that certain antibodies (and other types of therapeutic agents) efficiently lower and neutralize Aβ oligomers as well as amyloid seeds in vivo, followed by the rigorous design and meticulous execution of clinical trials in humans confirmed to have AD pathobiology and treated for at least 18 to 24 months, with validated markers of AD pathology and multiple cognitive and functional end points that confirm each other. Of special importance would be the development of fluid and imaging markers of synaptic dysfunction, since the latter is a particularly important correlate of AD pathobiology.

Efficient Epigenetic Clocks May Not Be Useful Epigenetic Clocks
https://www.fightaging.org/archives/2022/07/efficient-epigenetic-clocks-may-not-be-useful-epigenetic-clocks/

An epigenetic clock is a weighted algorithmic combination of the methylation status of various specific CpG sites on the genome, where the number produced matches well with chronological or biological age. It is constructed by applying machine learning techniques to epigenetic data, a catalogue of DNA methylation patterns across the full structure of the genome, taken from blood samples of mice or people at various ages. The early epigenetic clocks use hundreds of CpG sites, and therefore one might reasonably hypothesize that they reflect the entire breadth of the processes of aging. That turns out not to be true, but it was reasonable.

As work on the production of epigenetic clocks progressed, as well as the establishment of other clocks based on transcriptomic, proteomic, and other data, many groups have found highly optimized clocks that use very few CpG sites, less than a dozen. Further, it is possible to identify sites, when using such small numbers, that work the same way in mice, humans, and other mammalian species. This is desirable in one sense, in that such clocks are less costly to implement, particularly at scale. On the other hand, it is not reasonable to think that such clocks will reflect more than a tiny fraction of the processes of aging.

If all one cares about is to measure biological age absent intervention, then it really doesn't matter whether a clock measures only one or only a few of the underlying processes or dysfunctions of age. Absent intervention, all of the processes of aging proceed in parallel, so measuring just one or just a few is good enough. However, it is the case that every new approach to rejuvenation therapy will address only the one target mechanism, a limited portion of the contributions to degenerative aging. It is entirely plausible that an epigenetic clock will underestimate or overestimate the utility of a potential rejuvenation therapy, and the plausibility of that outcome increases as the number of CpG sites decreases. The most important future use for epigenetic and other clocks is to steer research and development towards larger effect sizes, more effective approaches to human rejuvenation. But we are not there yet.

Epigenetic Clocks for Mice Based on Age-Associated Regions That are Conserved Between Mouse Strains and Human

Precise measurement of aging is a prerequisite to identify parameters that may attenuate the aging process. It is fascinating that the DNA methylation (DNAm) patterns change in a highly reproducible and seemingly organized manner during aging of the organism. This epigenetic modification at the cytosine residues of CG dinucleotides (CpGs) impacts on chromatin organization, transcription factor binding, and gene expression. It is therefore anticipated that age-associated DNAm might be of immediate functional relevance for the aging process, albeit this remains to be proven. Today, epigenetic clocks are considered to be the most accurate biomarker for age predictions and there is sound evidence that they also capture aspects of biological aging that are independent from chronological age.

In this study, we used the recently released Infinium Mouse Methylation BeadChip to compare such epigenetic modifications in C57BL/6 (B6) and DBA/2J (DBA) mice. We observed marked differences in age-associated DNA methylation in these commonly used inbred mouse strains, indicating that epigenetic clocks for one strain cannot be simply applied to other strains without further verification. Interestingly, the CpGs with highest age-correlation were still overlapping in B6 and DBA mice and included the genes Hsf4, Prima1, Aspa, and Wnt3a. Furthermore, Hsf4, Aspa, and Wnt3a revealed highly significant age-associated DNA methylation in the homologous regions in human. Subsequently, we used pyrosequencing of the four relevant regions to establish a targeted epigenetic clock that provided very high correlation with chronological age in independent cohorts of B6 and DBA.

Larger signatures that comprise hundreds of CpGs may be more robust than targeted assays that only consider one or few CpGs, since they reflect a broader epigenetic pattern. BeadChip technology makes large signatures easily applicable since all relevant CpGs are addressed in each sample. However, adaptation and integration of different microarray datasets remains a major hurdle and age-predictors may become outdated if a BeadChip release is discontinued. It may therefore be advantageous to rather focus on individual CpGs by targeted methods, such as pyrosequencing, digital droplet PCR, or barcoded amplicon sequencing. These methods give very precise and reproducible results on single CpG level and facilitate fast and more cost-effective analysis. Notably, all 21 CpGs covered by our pyrosequencing assay provided very high correlation with age in all training and validation cohorts. Our four CpG epigenetic age prediction model thus now outperforms our previously published three CpG signatures. Other methods for age prediction in mice have reported lower correlations with a higher number of CpG sites (9-582).

Suggesting that 40% of Dementia is the Result of Lifestyle and Environment
https://www.fightaging.org/archives/2022/07/suggesting-that-40-of-dementia-is-the-result-of-lifestyle-and-environment/

Researchers here run the numbers to suggest that as much of 40% of the incidence of dementia is the result of lifestyle choices and environmental factors, and thus amenable to prevention. A lot of these line items are known to contribute to the chronic inflammation of aging, and evidence increasingly leans towards an important role for unresolved, lasting inflammation in the progression of neurodegenerative conditions. Much of the focus is on hypertension, the raised blood pressure that is very damaging to fragile tissues such as those of the brain. Hypertension can be controlled to a large degree via changes in diet, weight, and exercise.

How much all-cause dementia could be prevented in the United States? Researchers attribute 41 percent of dementia cases to 12 modifiable lifestyle factors. Obesity, high blood pressure, and lack of exercise accounted for the lion's share. This estimate is on par with a Lancet Commission report linking 40 percent of dementia cases worldwide to the same 12 risk factors: physical inactivity, excess alcohol consumption, obesity, smoking, hypertension, diabetes, depression, traumatic brain injury, hearing loss, few years of education, social isolation, and air pollution. However, the report pegged hearing loss, education, and smoking as the three largest ones.

In the U.S. data, the three most prevalent factors - obesity, hypertension, physical inactivity - also had the largest population attributable fraction (PAF), each accounting for 20 percent of dementia risk. Other common risk factors carried lower risk. Air pollution ranked fifth in prevalence but came in second to last as a risk factor, explaining only 2.2 percent of preventable dementia. Excessive alcohol consumption, defined as drinking more than 14 standard drinks per week, accounted for 0.7 percent. These "unweighted" numbers did not take into account that some risks correlate with each other. For example, physical inactivity increases a person's chances of gaining weight or having high blood pressure, or obesity increases a person's odds of developing diabetes.

Adjusting for such correlations, researchers calculated that each factor directly explained 0.5 to 7.0 percent of the total modifiable risk. Obesity, hypertension, and physical inactivity still came out on top, each accounting for about 7.0 percent. Diabetes was a close fourth, at approximately 4.5 percent.

Aubrey de Grey on Progress in SENS Rejuvenation Research
https://www.fightaging.org/archives/2022/07/aubrey-de-grey-on-progress-in-sens-rejuvenation-research/

In this recent interview with Aubrey de Grey touches on a number of areas of progress made by the research and development community in recent years, projects that lead towards rejuvenation therapies based on the Strategies for Engineered Negligible Senescence (SENS). In the SENS view, supported by a very sizable literature accumulated over the past century, aging is caused by underlying processes of damage accumulation. What we think of as aging is a diverse collection of downstream consequences of that damage. Periodically repairing the underlying damage, allowing the normal maintenance of the body to continue as it would in youth, remains the most promising approach to aging. Senolytic drugs to clear senescent cells are one example of a rejuvenation therapy based on SENS, and in animal models senolytics produce very impressive results on near all age-related conditions assessed to date.

Ariel VA Feinerman: Can you name the most big breakthrough in each SENS programme since our interview in 2017?

Aubrey de Grey: Well, let's see…

RepleniSENS: probably the initiation of a clinical trial in Japan using iPSC-derived dopaminergic precursors to cure Parkinson's Disease. Other such trials are imminent in the USA.

OncoSENS: definitely the main thing is 6-thiodeoxyguanine, or just THIO for short, which is essential "WILT 2.0". It turns telomerase into a suicide gene, killing cells quickly, rather than waiting for them to divide into telomere-less oblivion.

ApoptoSENS: I'd say it's the successful extension of mouse lifespan with a senolytic. It's a big surprise that just one SENS intervention can have a substantial lifespan effect when initiated late in life.

AmyloSENS: the definitive confirmation that immune therapies can eliminate amyloid in the Alzheimer's brain. Even though there is basically no cognitive benefit, it's a very important thing to know for the future, especially for other amyoloids that are more causal.

LysoSENS: definitely the success of our atherosclerosis team in developing a drug to extract oxidative cholesterol from plaques. That has now become a spinout company, Clarity Therapeutics.

GlycoSENS: the spinning-out of another company, Revel Pharmaceuticals. which is developing cross-link-breakers. That was the result of the pioneering work at Yale that we funded for several years.

MitoSENS: the main thing in our team is a new way to increase the amount of protein that our transferred genes make, but also it's really important that our work over the past few years has gained a lot of respect from mainstream experts who used to think it was never going to work.

Ariel VA Feinerman: Previously you have said that there are two types of epigenetic changes, reversible shift, which is a reaction to the cellular environment, and irreversible noise, which is stochastic. Now researchers claim that epigenetic changes are because of double strand breaks. This type is not shift or noise because this is stochastic and reversible using the Yamanaka factors (OSKM). Can you comment on this?

Aubrey de Grey: The problem is that OKSM doesn't only eliminate noise - it eliminates (very nearly) all epigenetic marks, whether noise or signal. The only reason it can be therapeutic is because doing just a little bit of that wiping of information seems to be OK - the cell can use the residual signal as a guide to rebuild the lost signal, whereas the proportion of the noise that was also removed is really gone. Sounds good! Except ... that in the body (even the young adult) there are a lot of cells that are most of the way to becoming cancerous. These cells are in what we can think of as an epigenetically fragile state: it doesn't take much to tip them over the edge, because their cell-cycle stabilisation defences are already damaged. So, all in all, I am currently quite pessimistic about the future of OKSM-based rejuvenation.

Ariel VA Feinerman: Is any progress with ALT cancer?

Aubrey de Grey: There has been plenty of progress in the past five years, yes, but not by us - indeed, the progress by others that has led to us deprioritising it. But there is still some way to go to find a generic approach to attacking it. I am optimistic, because ALT basically relies on the maintenance of an unstable equilibrium between DNA damage and repair, which should be vulnerable to other stressors.

Ariel VA Feinerman: How does THIO work? How can we protect stem cells from THIO?

Aubrey de Grey: THIO is a brilliant discovery. It works by turning telomerase into a suicide gene. Specifically, telomerase incorporates it into the telomere, but that disrupts the structure that lets the telomere do its job of preventing the cell's DNA repair machinery from joining chromosomes together. So chromosomes do get joined together, and that leads rapidly to cell death. Stem cells, even the most rapidly-dividing ones, have such tiny amounts of telomerase as compared to cancer cells that they are not significantly harmed by the dose and duration needed to kill a telomerase-positive cancer.

An Omics View of the Inflammation of Aging
https://www.fightaging.org/archives/2022/07/an-omics-view-of-the-inflammation-of-aging/

Aging is characterized by chronic inflammation, disruptive of cell and tissue function, a sizable contribution to the onset and progression of all of the common age-related conditions. The causes of this inflammation are known at the high level, such as the increasing presence of senescent cells and damage-associated molecular patterns, such as DNA debris from dead and dying cells. At the detail level, the real of genomics, transcriptomics, proteomics, and the other omics, much remains to be cataloged. There is the hope that a full map of inflammation in aging would point out more and better regulatory or signal molecules that could be targeted by therapies, but this type of approach has so far proven less effective than hoped, given the side-effects it produces. The goal of blocking only excessive inflammation, without blocking essential inflammation, requires a focus on the causes of inflammation, rather than sabotage of the initiation or progression of inflammation.

The immune system undergoes numerous and profound changes with aging. Hallmarks of immune aging are (a) a state of proinflammatory activation characterized by high circulating levels of proinflammatory cytokines - such as IL-6 and TNF-α - and localized tissue inflammation, and (b) an aberrant response to antigens and pathogens that could either be blunted, such as in flu vaccination, or excessive, such as in response to SARS-CoV-2. Considerable research in both animal models and humans has examined the causes and consequences of inflammaging. Although increased levels of inflammatory mediators (mostly IL-1, IL-6, TNF-α, and its receptors) are detected in all elderly individuals, higher levels of these biomarkers are associated with increased risk for many chronic conditions, including dementia, disability, and physical frailty. Inflammation's causal role in cardiovascular disease was established by the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated that IL-1β inhibition reduced the risk of cardiovascular events versus the placebo, particularly in participants whose IL-6 levels were initially elevated.

Mechanisms identified as hallmarks of aging biology and immune cell dysfunction have all been hypothesized as causes of inflammation. Aging researchers now recognize that measuring a few cytokines in circulation fails to capture the complexity and potential ramifications of inflammaging. Immune cells in tissues, particularly lymphocytes and resident macrophages, show tissue-specific age-related changes likely connected to specific pathological processes. By measuring hundreds or thousands of molecules in a few drops of blood, scientists are attempting to identify (a) signatures of accelerated aging that are both informative of the complexity and diversity of the response and predictive of health outcomes and (b) key molecules and molecular mechanisms that can be targeted for intervention.

Given the extreme complexity of inflammaging, we focus herein on a few topics that have attracted considerable attention and controversy in the field. First, we discuss cellular senescence as a source of local and systemic inflammation. We highlight evidence that mitochondrial dysfunction is a nexus that binds impaired mitophagy with DNA damage and cellular senescence to ultimately foster a chronic inflammatory state. We then summarize efforts to identify circulating signatures of inflammation through "omics." Finally, we review emerging data indicating that inflammation is involved in brain aging and dementia. Our intent is to discuss the causes and consequences of inflammaging and to enrich the research agenda toward the development of new therapeutic strategies.

Inflammatory Pathways Triggered by the Aging Gut Microbiome Converge on NF-κB
https://www.fightaging.org/archives/2022/07/inflammatory-pathways-triggered-by-the-aging-gut-microbiome-converge-on-nf-%ce%bab/

While more knowledge is always a good thing in the long run, it is unclear as to what exactly can be done about age-related chronic inflammation in the near term with a better map of the regulatory processes that initiate, sustain, and suppress inflammation. The state of knowledge today strongly suggests that excessive, unwanted inflammation and necessary, important inflammation both run through the same systems of signaling between and within cells. Therapies based on interfering in more critical portions of that signaling can reduce inflammation, and indeed a number of such drugs already exist, but they have the serious side-effect of also interfering in the vital activities of the immune system. It seems likely that the practical way forward is to remove the causes of inflammation rather than suppressing the mechanisms of inflammation. In the case of inflammation provoked by the aging of the gut microbiome, there are comparatively simple approaches that can reset the balance of populations and reduce the presence of inflammatory microbes, such as fecal microbiota transplantation. It only remains to bring them into common medical practice.

Of the distinct niches colonized by our microbiota within or on us, the gastrointestinal tract harbours the most complex microbiota, consisting of bacteria, fungi, viruses, archaea, and protozoa, and acts as a hotspot for host-microbe interactions. The host through evolution and adaptation has developed diverse mechanisms to distinguish between the microbial symbionts and pathogens and respond accordingly by balancing between tolerance and inflammation. The first step of this interaction is mediated by pattern recognition receptors (PRRs), which sense microorganisms through conserved molecular structures. Several families of PRRs have now been well studied, including the Toll-like receptors (TLRs), the nucleotide-binding oligomerization (NOD)-like receptors (NLRs), the C-type lectin receptors, and the RIG-I-like receptors (RLRs).

Once the microbial signatures are recognized by the host, usually a transcriptional response follows, which determines the outcome of this interaction and is critical for maintaining the balance between homeostasis and inflammation. It is at this stage that members of the nuclear factor kappa B (NF-κB), play a crucial balancing act by maintaining tolerance towards the endogenous symbionts, hence establishing homeostasis while activating inflammatory pathways in response to abnormal changes in the microbiome, "dysbiosis", or pathogenic invasion. Most of the cellular PRRs such as TLRs, NLRs and RLRs after sensing microbial signatures follow distinct pathways, which ultimately converge to stimulate NF-κB, suggesting NF-κB's central role in host response to microbes.

The balance in NF-κB response to microbial signatures becomes crucial for host health particularly during ageing and is often linked to ageing associated diseases. Ageing is associated with an overall decline in host organ functions, which changes host requirements and the dynamics between the host and its microbiota, leading to alterations in microbiome composition and diversity. These age-related microbiota transmutations can either be beneficial with the enrichment of health associated microbes and promote healthy ageing or may lead to severe imbalances leading to a potentially detrimental condition, termed dysbiosis. Ageing-associated dysbiosis usually triggers host immune responses, particularly the innate arm of it, since adaptive immunity typically declines with age, a phenomenon termed immunosenescence. This elevated basal level of innate immune responses during ageing leads to sustained inflammation, a condition known as inflammaging, which contributes to increased risk of developing age-related diseases. NF-κB signaling is a central player in this process as it integrates microbial cues via PRRs and in turn orchestrates innate immune responses.

PEDF in the Retina, an Example of the Slow Pace of Progress
https://www.fightaging.org/archives/2022/07/pedf-in-the-retina-an-example-of-the-slow-pace-of-progress/

Fifteen years ago, initial clinical trials were underway for a gene therapy to upregulate PEDF expression in the retina of patients with macular degeneration, the result of years of work on the involvement of PEDF expression in retinal aging. Today, we can see researchers still working with animal models on the fundamental question of whether or not PEDF expression is actually relevant in the aging of the retina. This sort of thing isn't uncommon. Research into the role and relevance of any given protein can span decades, and still go nowhere. This is not a field noted for its speed, or its ability to focus on approaches that work well versus those that are marginal.

The retina is composed of layers of cells that function together to detect and process light signals, which the brain uses to generate vision. The retina's light-sensing photoreceptors sit above the retinal pigment epithelium (RPE), a layer of support cells. The RPE nourishes photoreceptors and recycles pieces of the photoreceptor cells called "outer segments," which get used up and their tips shed each time photoreceptors detect light. If the RPE cannot provide recycled components of older outer segment tips back to photoreceptors, these cells lose their ability to make new segments, and eventually become unable to sense light. And without nutrients supplied by the RPE, photoreceptors die. In people with macular degeneration or certain types of retinal dystrophies, senescence, or death of RPE cells in the retina leads to vision loss.

Previous work has shown that PEDF protects retinal cells, preventing both damage to the cells and abnormal growth of blood vessels in the retina. RPE cells produce and secrete the PEDF protein. The protein then binds to its receptor, PEDF-R, which is also expressed by RPE cells. Binding by PEDF stimulates PEDF-R to break down lipid molecules, key components of the cell membranes that enclose photoreceptor outer segments and other cellular compartments. This breakdown step is a key part of the outer segment recycling process. And while researchers have known that PEDF levels drop in the retina during the aging process, it was not clear whether this loss of PEDF was causing, or merely correlated with, age-related changes in the retina.

To examine the retinal role of PEDF, researchers studied a mouse model that lacks the PEDF gene, finding that the RPE cell nuclei were enlarged, which may indicate changes in how nuclear DNA is packed. The RPE cells also had turned on four genes associated with aging and cellular senescence, and levels of the PEDF receptor were significantly below normal. "One of the most striking things was this reduction in the PEDF receptor on the surface of the RPE cells in the mouse lacking the PEDF protein. It seems there's some sort of feedback-loop involving PEDF that maintains the levels of PEDF-R and lipid metabolism in the RPE."

Mosaic Loss of Y Chromosome Provokes Macrophage Dysfunction and Inflammation
https://www.fightaging.org/archives/2022/07/mosaic-loss-of-y-chromosome-provokes-macrophage-dysfunction-and-inflammation/

Stochastic mutational damage is thought to be problematic where it occurs in stem cells and progenitor cells, and can thus spread widely. A more severe form of such damage is the loss of the entire Y chromosome in men. Researchers here provide evidence, using an engineered mouse lineage, for this to make macrophages more inflammatory, accelerating fibrosis and dysfunction in the heart. This in turn raises mortality, which might explain the observed association between loss of the Y chromosome and increased incidence of age-related disease in humans. Inflammation accelerates all of the common fatal age-related conditions, and dysfunction in immune cells is a real problem in this context.

Why a condition that frequently occurs in aging men, in which an increasing number of hematopoietic cells display a loss of the Y chromosome, is associated with increased risk of mortality and age-related diseases is now a little clearer, thanks to work in mice. This condition - known as mosaic loss of Y chromosome, or mLOY - is a major risk factor for heart failure and cardiac fibrosis in men growing older, according to the study, which includes prospective data from the UK Biobank. The study also revealed that a neutralizing antibody could reverse some cardiac impacts caused by mLOY.

The Y chromosome has been long considered a "genetic wasteland," and beyond biological sex determination, there is little understanding of its functional role. Nevertheless, mLOY in blood cells has been linked to increased risk for mortality, cardiovascular disease, and other age-related disorders. In human somatic cells, mLOY is the most commonly acquired mutation in the male's genome. However, a relationship between mLOY and pathogenesis has not yet been established.

Using CRISPR-Cas9, researchers developed a mouse model of hematopoietic mLOY by reconstituting their bone marrow with cells lacking the Y chromosome. They discovered that these mice displayed increased mortality and were more prone to age-related cardiac fibrosis and decreased cardiac function. According to the findings, bone marrow-derived mLOY macrophages that infiltrate the heart trigger high transforming growth factor β1 (TGF-β1) activity, which leads to fibroblast proliferation and accelerated cardiac tissue fibrosis. Treatment with a TGF-β1 neutralizing antibody was shown to ameliorate these harmful effects. What's more, a prospective study in human patients showed that those with mLOY in blood were also at a greater risk for cardiovascular dysfunction and associated mortality.

Inundated with an Ideology of Death-Acceptance
https://www.fightaging.org/archives/2022/07/inundated-with-an-ideology-of-death-acceptance/

Is it a challenge to advocate for greater funding for rejuvenation research, a challenge to persuade people that significantly extending healthy human life spans is possible, plausible, and potentially imminent, because we are all relentlessly taught from an early age that death is to be accepted? Our myths, our ever-rewoven heritage of stories modern and ancient, propagandize for aging and death. Our cultures are replete with tales in which longevity is a punishment, and heroes are castigated for even trying to seek a longer life. This is an interesting question: to what degree are we controlled and constrained by the expectations taught to us, directly and indirectly, by the stories that wind their way through life around us?

I suggest that we have been culturally conditioned to think that it is virtuous to accept aging and death. We are taught to believe that although aging and death seem gruesome, they are what is best for us, all things considered. This is what we are supposed to think, and the majority accept it. I call this the Wise View because death acceptance has been the dominant view of philosophers since the beginning. Socrates compared our earthly life to an illness and a prison and described death as a healer and a liberator. The Buddha taught that life is suffering and that the way to escape suffering is to end the cycle of birth, death and rebirth. Stoic philosophers from Zeno to Marcus Aurelius believed that everything that happens in accordance with nature is good, and that therefore we should not only accept death but welcome it as an aspect of a perfect totality.

Many of the stories we tell promote the Wise View. One of the earliest known pieces of literature, the Epic of Gilgamesh, follows Gilgamesh on a quest for eternal life ending with the wisdom that death is the destiny of man. Today we learn about the tedium of immortality from the children's book Tuck Everlasting by Natalie Babbitt, and we are warned about the vice of wanting to resist death in other books and films such as J.K Rowling's Harry Potter, where Voldemort must kill Harry as a step towards his own immortality; C.S. Lewis' The Chronicles of Narnia where the White Witch has gained immortal youth and madness in equal measures; J.R.R. Tolkien's Lord of the Rings trilogy where the ring extends the wearer's life but can also destroy them, as exemplified by the creep Gollum; and Doctor Strange where life extension is the one magical power that is taboo.

We are inundated and saturated with an ideology of death-acceptance. The Wise View resonates with us partly because we think that there is nothing we can do about aging and death, so we do not want to wish for what we cannot have. Youth and immortality are sour grapes to us. Believing that death is, all things considered, not such a bad thing, protects us from experiencing our aging and approaching death as a gruesome tragedy. This need to escape the thought that we are heading towards a personal catastrophe explains why many are so quick to accept arguments against radical life extension, despite their often glaring weaknesses.

A Lipid Based Aging Clock
https://www.fightaging.org/archives/2022/07/a-lipid-based-aging-clock/

All biological data changes with age, and enormous sets of such data can be recorded with comparative ease these days. Any sufficiently large set of data can be processed via suitable machine learning approaches in order to produce clocks that correlate with biological age. Some are better than others, some appear to be more sensitive or less sensitive to certain aspects or processes of aging. At the end of the day, these efforts will likely prove useful, but so far they have yet to result in the ability to reliably and rapidly assess a potential rejuvenation therapy for its ability to slow or reverse aging. A clock will always deliver a number, but since the connection between the clock and underlying processes of aging remains unclear, it also remains unclear as to whether that number will in fact usefully reflect changes in biological age produced by a given therapy.

Complexity is a fundamental feature of biological systems. Omics techniques like lipidomics can simultaneously quantify many thousands of molecules, thereby directly capturing the underlying biological complexity. However, this approach transfers the original biological complexity to the resulting datasets, posing challenges in data reduction and analysis. Aging is a prime example of a process that exhibits complex behaviour across multiple scales of biological organisation. The aging process is characterised by slow, cumulative and detrimental changes that are driven by intrinsic biological stochasticity and mediated through non-linear interactions and feedback within and between these levels of organization (ranging from metabolites, macromolecules, organelles and cells to tissue and organs).

Only collectively and over long timeframes do these changes manifest as the exponential increases in morbidity and mortality that define biological aging, making aging a problem more difficult to study than the aetiologies of specific diseases. But aging's time dependence can also be exploited to extract key insights into its underlying biology. Here we explore this idea by using data on changes in lipid composition across the lifespan of an organism to construct and test a LipidClock to predict biological age in the nematode Caenorhabditis elegans. The LipidClock consist of a feature transformation via Principal Component Analysis followed by Elastic Net regression and yields a Mean Absolute Error of 1.45 days for wild type animals and 4.13 days when applied to mutant strains with lifespans that are substantially different from that of wild type. Gompertz aging rates predicted by the LipidClock can be used to simulate survival curves that are in agreement with those from lifespan experiments.

Detecting Alzheimer's Disease Seventeen Years in Advance
https://www.fightaging.org/archives/2022/07/detecting-alzheimers-disease-seventeen-years-in-advance/

Alzheimer's disease develops over twenty years or more, a slow growth of amyloid-β aggregates in the brain that sets the stage for a feedback loop of inflammation, cellular senescence, and tau aggregation that causes severe pathology and eventual death. As researchers demonstrate here, patients who will very likely go on to develop Alzheimer's disease many years in the future can be identified quite early. The mechanisms that will inexorably lead to the condition, and the lifestyle choices that adjust the pace of progress, are in place as much as two decades prior to diagnosis with the clinical stage of the disease. This produces signatures in the bloodstream that can be seen with simple tests, or at least the tests are simple once those signatures have been identified. It is that identification that has proven challenging, but the research community has made rapid progress on this front in the past few years.

The dementia disorder Alzheimer's disease has a symptom-free course of 15 to 20 years before the first clinical symptoms emerge. Using an immuno-infrared sensor, a research team is able to identify signs of Alzheimer's disease in the blood up to 17 years before the first clinical symptoms appear. The sensor detects the misfolding of the protein biomarker amyloid-beta. As the disease progresses, this misfolding causes characteristic deposits in the brain, so-called plaques.

The researchers analysed blood plasma from participants in the ESTHER study for potential Alzheimer's biomarkers. The blood samples had been taken between 2000 and 2002 and then frozen. At that time, the test participants were between 50 and 75 years old and hadn't yet been diagnosed with Alzheimer's disease. For the current study, 68 participants were selected who had been diagnosed with Alzheimer's disease during the 17-year follow-up and compared with 240 control subjects without such a diagnosis. The team aimed to find out whether signs of Alzheimer's disease could already be found in the blood samples at the beginning of the study.

The immuno-infrared sensor was able to identify the 68 test subjects who later developed Alzheimer's disease with a high degree of test accuracy. For comparison, the researchers examined other biomarkers with the complementary, highly sensitive SIMOA technology - specifically the P-tau181 biomarker, which is currently being proposed as a promising biomarker candidate in various studies. "Unlike in the clinical phase, however, this marker is not suitable for the early symptom-free phase of Alzheimer's disease. Surprisingly, we found that the concentration of glial fibre protein (GFAP) can indicate the disease up to 17 years before the clinical phase, even though it does so much less precisely than the immuno-infrared sensor." Still, by combining amyloid-beta misfolding and GFAP concentration, the researchers were able to further increase the accuracy of the test in the symptom-free stage.

Autophagy as a Therapeutic Target
https://www.fightaging.org/archives/2022/07/autophagy-as-a-therapeutic-target/

Plenty of evidence points to improvement in the cellular maintenance processes of autophagy (primarily macroautophagy and chaperone-mediated autophagy) as the primary mechanism by which the response to mild stress improves health and extends life. Autophagy recycles broken molecules and damaged structures in the cells. More recycling implies better function, a lesser burden of damage and dysfunction at any given time. This underlies the extension of life span resulting from calorie restriction, for example. Researchers are interested in the development of drugs that mimic these stress responses by artificially upregulating autophagy. mTOR inhibitors achieve this goal, as do other calorie restriction mimetic drugs, but the effects in humans are so far modest, producing effects that, on the whole, compare poorly to the outcome of structured exercise programs, or the practice of calorie restriction itself.

Autophagy refers to a process in which the intracellular components such as abnormal proteins, damaged organelles, foreign pathogens, and other cellular components are degraded via lysosome. This catabolic process is evolutionarily conserved from yeast to mammalian cells. In mammalian cells, autophagy has been traditionally classified into the following three main types, macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Among them, macroautophagy is featured by the formation of a unique double-membrane organelle, the autophagosome. In contrast, both microautophagy and CMA bypass autophagosome formation and the cargos are directly delivered to a lysosome.

At present, the majority of the autophagy research is on macroautophagy, or referred as autophagy hereafter in this review. On the other hand, depending on the nature of the cargos, autophagy can be categorized into general/nonselective and selective autophagy. For nonselective autophagy, the cellular cargos are engulfed into the autophagosomes randomly, a process usually induced by general stress conditions such as nutrient starvation. In contrast, selective autophagy refers to selective degradation of specific cargos, and so far, there are many types of selective autophagy being studied, such as mitophagy (selective degradation of mitochondria), endoplasmic reticulum (ER)-phagy (selective degradation of ER), aggrephagy (selective degradation of protein aggregates), and xenophagy (selective degradation of invaded pathogens), just to name a few.

It has been well studied that autophagy have important functions in various biological processes, such as cell survival and cell death, inflammation and immunity, development and differentiation, metabolic homeostasis, and so on. As such, autophagy is known to be closely implicated in the pathogenesis of human diseases. In this review, we will mainly focus on nonselective macroautophagy to provide a systematic discussion on the latest development on the molecular mechanisms, the implication of autophagy in important human diseases including cancer, neurodegeneration, metabolic diseases, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, cardiovascular diseases, and aging. Moreover, we will also discuss the therapeutic potential of targeting autophagy in human diseases. Finally, we will highlight the challenges the autophagy research field is facing and the directions of future study.