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

• An Overview of Companies Targeting Mitochondrial Dysfunction in Aging
• The Future of Human Longevity will be Very Different from the Past
• Targeting of Telomere Lengthening Processes will be the Basis of the Next Generation of Cancer Therapies
• The Present Understanding of the Relationship Between Growth Hormone and Longevity
• Prevalence of Cellular Senescence May Explain the Inverse Correlation Between Cancer and Neurodegeneration
• Flies that Choose a Poor Diet Have a Shorter Lifespan than those Forced into a Poor Diet
• Prevalence of Ischemic Scars in the Retina Correlates with Heart Disease Risk
• Immunoglobulin-M Antibodies Reduce Risk of Thrombosis by Binding to Extracellular Vesicles that Induce Coagulation
• The Popular Science Media Fails to Distinguish Between Potentially High Yield and Probably Low Yield Treatments for Aging
• Raised Levels of Amyloid-β in the Retina Impair Lysosomal Function
• Estimating that Technological Progress Accounts for Half of the Gains in Life Span Since the 1960s
• Thoughts on Medical Progress and Living Longer
• Improving Autophagy to Restore Hematopoietic Function in Aged Individuals
• SPACs for Longevity Companies: Helpful or Not?
• Mitochondrial Transplantation as a Treatment for Heart Disease

An Overview of Companies Targeting Mitochondrial Dysfunction in Aging
https://www.fightaging.org/archives/2021/03/an-overview-of-companies-targeting-mitochondrial-dysfunction-in-aging/

Today's materials are a helpful overview of the brace of biotech companies working to slow or reverse aspects of mitochondrial aging. Mitochondria play a central role in core cellular processes and are important in degenerative aging. Every cell contains a herd of hundreds of mitochondria, the descendants of an ancient symbiosis between the first cells and bacteria that could help them survive. Each mitochondrion contains one or more copies of mitochondrial DNA, a small remnant of the original bacterial genome, just a few genes that evolution has yet to move to the cell nucleus. The mitochondrial population of a cell is dynamic: constant fission, fusion, swapping of protein machinery, and destruction by the quality control process of mitophagy when worn and damaged.

While mitochondria have many roles, their primary task is the packaging of the chemical energy store molecule ATP. This powers cellular operations, but its production is an energetic process by that produces a flux of oxidizing molecules as a byproduct. These molecules damage protein machinery in the cell via oxidative reactions, a form of damage that is constantly repaired, and which cells maintain antioxidant defenses to minimize. At low levels this is a beneficial signal for the cell to engage in greater repair efforts. At high levels it harms a cell.

There are several classes of mitochondrial problem that emerge with age. Firstly ATP production is reduced. Mitochondrial dynamics change: mitochondria become resistant to mitophagy, and falter in their tasks. Secondly, these changes also result in a greater production of oxidative molecules. Thirdly, mitochondrial DNA is less well protected and repaired than nuclear DNA, and some forms of mutational damage can produce malfunctioning mitochondria that outcompete their functional peers, taking over cells. This converts healthy cells into pathological exporters of oxidative molecules, damaging surrounding tissues through a range of related mechanisms. These include raised levels of oxidized cholesterol molecules in the bloodstream, contributing to the development of atherosclerosis by encouraging dysfunction in the macrophage cells responsible for keeping blood vessel walls clear of atherosclerotic lesions.

Something should be done about mitochondrial dysfunction in aging and age-related disease. It is very clearly implicated in the onset and progression of numerous age-related conditions. Numerous approaches are under consideration, with varying degrees of expected utility and progress towards availability. NAD+ upregulation, for example, attempts to correct one of the many observed changes in mitochondrial biochemistry. As presently practiced, using vitamin B3 derivative compounds, it is most likely less effective than structured exercise programs at achieving its goal. At the other end of the spectrum lie advanced biotechnologies in the early stages of development, such as copying mitochondrial genes into the cell nucleus via gene therapy in order to make mitochondrial DNA mutation irrelevant to aging. A great many other approaches lie between the two.

#022: A Map of Mitochondria Longevity Companies (PART 1)

In this newsletter, we're going to take a look at all the longevity biotech companies that are developing therapies that target mitochondrial dysfunction - one of the "Hallmarks of Aging". Mitochondria companies make up one of the biggest subcategories in longevity biotech. This makes sense as mitochondria are an extremely critical component of our cells. There are ~20+ longevity mitochondria companies currently, ranging from early stage-startups to Nasdaq-listed public companies. From small molecule drugs to gene therapies and mitochondrial transfusions. Seven of the companies are in clinical trials today.

Aging is not an accepted clinical indication (yet). So the current playbook for longevity biotech companies is to target a disease that shares the same underlying cause as one of the hallmarks/targets of aging for their first clinical trials and expand from there. Usually, this means an age-related disease or a rare genetic disease. Mitochondrial dysfunction is implicated in many diseases of aging. Longevity companies that target mitochondrial dysfunction generally choose clinical indications such as: mitochondrial diseases caused by mitochondrial DNA mutation or nuclear DNA mutations (LHON, Pearson syndrome, etc), muscle dystrophy diseases or muscle loss (Duchenne muscular dystrophy, Becker muscular dystrophy, sarcopenia), metabolic disorders (NASH, Obesity, NAFLD, Type 2 Diabetes), neurodegenerative disease (Alzheimer's, Parkinson's, etc), or conditions linked to oxidative damage (ischemia-reperfusion injury).

#022: A Map of Mitochondria Longevity Companies (PART 2)

Mitochondria are complex. It's still an open question on how they drive aging. Hallmarks of Mitochondrial Aging? Mitochondria have their own DNA, membranes, ribosome, move around (sometimes outside of the cell!), undergo fission and fusion, and provide one of the most critical cellular functions. Since they are almost like their own organism they probably deserve their own "Hallmarks of (Mitochondria) Aging" paper. But just like the original Hallmarks paper, it will be filled with many correlations and questions while causation is not always clear.

Mitochondrial transfer is very promising. I'll admit I am biased towards replacement therapies for anti-aging when it makes sense. It's a clean philosophical approach that lends itself to engineering more than traditional drug development. And unlike stem cell therapies or cellular transplants mitochondria can be replaced easily without the need for extracellular scaffolding or any kind of extra in situ differentiation. There will likely be a number of challenges to work out, though (sourcing allogeneic mitochondria, systemic distribution, determining long-term side effects, etc). One caveat: It is possible that transplanting healthy mitochondria into an old and dysfunctional cellular environment will quickly impair the transplanted organelles. Also, we need to consider the microtubules mitochondria use to move around the cell.

Protect mitochondrial DNA or remove mutations? GenSight Biologics is definitely one of the most interesting biotech companies I have ever stumbled upon. And while their therapies aren't considered anti-aging at the moment (save for GS020 for dry AMD), the technology is a step towards possibly solving the problem of mitochondrial mutations. But even here it is not clear whether it is more important to protect mitochondrial DNA from new mutations or stop already mutated mitochondrial DNA from accumulating via clonal expansion (like Shift Bioscience). Some researchers have also proposed using various DNA editing techniques (TALENS, Zinc Finger Nuclease, CRISPR) to destroy mutant mitochondrial DNA.

The Future of Human Longevity will be Very Different from the Past
https://www.fightaging.org/archives/2021/03/the-future-of-human-longevity-will-be-very-different-from-the-past/

Human life expectancy has increased through two distinct process; firstly a reduction in child mortality, and second a reduction in the burden of damage accumulated over an adult life span. Control of infectious disease has played a large role in both components of gains in life expectancy. The trend has been slow. In recent decades, something like 0.2 years of life expectancy at birth and 0.1 years of remaining life expectancy at age 60 have been added with each passing calendar year.

Life expectancy is an artificial measure, of course: it is the length of life remaining, on average, assuming that nothing changes in the state of medical science and public health practices. But there are always improvements. At present, the medical research community is shifting from a paradigm in which the mechanisms that cause aging were ignored, to a paradigm in which the mechanisms that cause aging are deliberately targeted. Meaningful slowing and reversal of degenerative aging are now on the table as options for the years ahead. This will cause considerable, and welcome, disruption to the slow historical increase in life expectancy. The future is bright.

Increasing life expectancy - the rise of longevity

A recent study analysed data from the Human Mortality Database (HMD), specifically looking at the probability of death at a given age. For various countries, including the US, Sweden, and Japan, individuals over 50 years had their mortality postponed, on average, by a decade for every age group (50s, 60s, 70s, etc.) from 1967 to 2017. In the example of Sweden, mortality remained constant more or less over the 19th and 20th centuries, until 1950 where an international life expectancy revolution took place.

This could be due to the colossal medical advancements that took place: the discovery of the structure of DNA, novel vaccines, the first successful kidney transplant, a novel antibiotic tetracycline, the first oral contraceptive and the invention of the internal pacemaker. Since then, life expectancy increased almost linearly at a rate of 2.5 years per decade all over the world. This same trend is observed in the longevity leader - Japan. Undoubtedly, the improvements in mortality stem from postponing it and thus prolonging both lifespan and healthspan. People are living longer due to being healthier and thus aging diseases are pushed back, developing later in life.

There are three predominant views on which longevity researchers speculate about the future of life expectancy: 1) life expectancy will rise, but more slowly that in the past due to reaching the 'limit'; 2) the same 2.5 year per decade increase in life expectancy will continue as in the past; 3) life expectancy will rise at a much faster rate due to biomedical advances, as previously seen in the 1950s. The future for longevity will differ from the past, as various mortality improvements play their part. A more effective public health strategy, along with devising treatments to cure aging diseases, such as dementia and cancer, would push out the current limits of healthspan and lifespan. Furthermore, developments in precision medicine, nanotechnology, regenerating tissues, and research on the biology of aging may all lead to slowing rates of aging.

Targeting of Telomere Lengthening Processes will be the Basis of the Next Generation of Cancer Therapies
https://www.fightaging.org/archives/2021/03/targeting-of-telomere-lengthening-processes-will-be-the-basis-of-the-next-generation-of-cancer-therapies/

Telomeres are repeated DNA sequences that form the end caps of chromosomes. A little of their length is lost with each cell division, and cells self-destruct or become senescent and cease replication when telomeres become too short. This is a part of the Hayflick limit on cell replication: near all cells in the body can only divide a limited number of times. Stem cells are the first exception, using telomerase to extend telomeres. Cancer cells are the second exception, employing either telomerase or the alternative lengthening of telomeres (ALT) mechanisms that do not operate in normal cells. Telomere lengthening is a universal mechanism in cancer, and thus there is considerable interest in producing a single class of treatment, based on interference in telomere lengthening, that can potentially shut down all cancers.

The original vision for whole-body interdiction of telomere lengthening, a part of the SENS rejuvenation research agenda, was to turn off the processes that lengthen telomeres throughout the body. Perhaps temporarily, or, in a more futuristic option, perhaps permanently when deployed in conjunction with periodic replacement of stem cell populations. Since the original proposition was put forward, research into ALT hasn't made all that much progress, perhaps because only 10% of cancers exhibit this behavior. Research into interfering with telomerase-based telomere lengthening has progressed, however, and diversified into a number of interesting lines of work. All of these seem likely to be targeted to cancer cells, either as an inherent result of the mechanism, or by combining the therapy with a selective delivery system.

One recent example of many is the work of Maia Biotechnology, building on an approach that sabotages telomerase-based telomere lengthening in a subtle way that has the outcome of killing cells. Today's research materials are another example of a program at an earlier stage of exploration, more focused on an indirect approach to reducing telomerase activity, one that can involve signaling applied outside the cell. This makes it an attractive basis for the development of therapies.

Researchers discover how telomere involvement in tumour generation is regulated

Researchers have in the past provided evidence to suggest that shelterins, proteins that wrap around telomeres and act as a protective shield, might be therapeutic targets for cancer treatment. Subsequently, they found that eliminating one of these shelterins, TRF1, blocks the initiation and progression of lung cancer and glioblastoma in mouse models and prevents glioblastoma stem cells from forming secondary tumours. Now researchers go one step further and describe for the first time how telomeres can be regulated by signals outside the cell that induce cell proliferation and have been implicated in cancer. The finding opens the door to new therapeutic possibilities targeting telomeres to help treat cancer.

Researchers have outlined a link between TRF1 and the PI3K/AKT signalling pathway. This metabolic pathway, which also encompasses mTOR, is one of the pathways most frequently affected in numerous tumorigenic processes. However, it was not known whether preventing TRF1 regulation by this pathway can have an impact on telomere length and its ability to form tumours. AKT acts as a transmitter of extracellular signals triggered by, among others, nutrients, growth factors, and immune regulators, to the interior of cells.

Researchers modified the TRF1 protein in cells to make it unresponsive to AKT, using the gene-editing tool CRISPR/Cas9. This way, TRF1 and the telomeres became invisible to any extracellular signals transmitted by AKT. Telomeres in these cells shortened and accumulated more damage; most importantly, the cells were no longer able to form tumours, indicating that telomeres are important targets of AKT and its role in cancer development.

The paper shows that telomeres are among the most important intracellular targets of the AKT pathway to form tumours, since, although neither the function of AKT nor of any of the thousands of proteins that are regulated by it was altered, only blocking AKT's ability to modify telomeres was sufficient to slow tumour growth. The next step will be to generate genetically modified mice with telomeres that are invisible to AKT. The authors anticipate that these mice will be more resistant to cancer.

AKT-dependent signaling of extracellular cues through telomeres impact on tumorigenesis

The telomere-bound shelterin complex is essential for chromosome-end protection and genomic stability. Little is known on the regulation of shelterin components by extracellular signals including developmental and environmental cues. Here, we show that human TRF1 is subjected to AKT-dependent regulation. To study the importance of this modification in vivo, we generate knock-in human cell lines carrying non-phosphorylatable mutants of the AKT-dependent TRF1 phosphorylation sites by CRISPR-Cas9.

We find that TRF1 mutant cells show decreased TRF1 binding to telomeres and increased global and telomeric DNA damage. Human cells carrying non-phosphorylatable mutant TRF1 alleles show accelerated telomere shortening, demonstrating that AKT-dependent TRF1 phosphorylation regulates telomere maintenance in vivo. TRF1 mutant cells show an impaired response to proliferative extracellular signals as well as a decreased tumorigenesis potential. These findings indicate that telomere protection and telomere length can be regulated by extracellular signals upstream of PI3K/AKT activation, such as growth factors, nutrients, or immune regulators, and this has an impact on tumorigenesis potential.

The Present Understanding of the Relationship Between Growth Hormone and Longevity
https://www.fightaging.org/archives/2021/03/the-present-understanding-of-the-relationship-between-growth-hormone-and-longevity/

Growth hormone treatments (and other hormone therapies) have a legitimate use in patients suffering excessively low hormone levels due to one or another cause. They have also long been overhyped and aggressively marketed by the anti-aging medicine community, not a field noted for its adherence to standards of truth and scientific accuracy. At the same time, the scientific evidence has consistently shown that aging is accelerated by higher levels of growth hormone. Tall people exhibit a modestly greater degree of age-related disease and mortality, for example, while the longest-lived mice are those with genetically engineered disruption of growth hormone function.

So what to make of this? There are obviously differences in the manifestations of aging in mice and humans, going beyond the obvious divergence in life span, despite the fact that the root causes are the same forms of cell and tissue damage in both species. The damage can be of a similar class, but different in detail, such as the identity of cross-links that cause loss of tissue elasticity. The important cross-linking molecules in mice and humans are quite different, but both contribute to stiffening of arteries and hypertension. The systems that react to damage or are made dysfunctional by it are different enough to react in different ways: mice have a far more plastic life span, capable of larger relative increases in longevity in response to improved cell maintenance or environmental factors such as calorie intake. A calorie restricted mouse and a calorie restricted human exhibit broadly similar short-term metabolic changes, but only the mouse lives 40% longer.

Growth Hormone and Aging: New Findings

In an earlier article, we presented the evidence that growth hormone (GH) has an important role in the control of aging and longevity. Much of the evidence for this role of GH was derived from studies of mice with spontaneous or experimentally induced mutations affecting the somatotropic axis and transgenic mice with chronic increase in circulating GH levels. Results of these studies indicated that (i) major elevation of GH levels accelerates aging and shortens life; (ii) stimulatory actions of normal (physiological) GH levels on growth, maturation, and fecundity involve costs in terms of the rate of aging and average as well as maximal longevity; and (iii) suppression of GH signaling slows the process of aging, increases healthspan, and remarkably extends longevity at the expense of reduced growth, delayed puberty, diminutive adult body size, and reduced fecundity. Importantly, these effects of GH on aging as well as the associated trade-offs were shown to apply to normal mice (animals without genetic modifications) and to other mammalian species.

In humans, familial longevity is associated with reduced GH secretion, and height, a strongly GH-dependent trait, is negatively correlated with longevity in many (although not all) of the examined populations. Hereditary conditions of isolated GH deficiency (IGHD) or GH resistance do not extend human longevity, but appear to extend healthspan and provide strong, and in some cases complete, protection from age-associated diseases. Pathological elevation of GH levels in the syndrome of acromegaly reduces both healthspan and life expectancy, likely reflecting acceleration of the aging process.

Paradoxically, recombinant GH treatment of middle aged or elderly subjects, in whom secretion of GH is naturally reduced, can have beneficial effects on body composition along with subjective improvement in various aspects of the quality of life. Beneficial effects of insulin-like growth factor I (IGF-I), a key mediator of GH actions on various aging-associated traits, support the notion that GH can act as an anti-aging agent. However, age is not among the approved indications for GH therapy and side effects and risks of GH therapy are generally believed to outweigh known or hoped-for benefits.

Available evidence indicates that most of the aging-related effects of GH which were discovered in laboratory mice apply to other mammals, including humans, but important species differences also exist. We speculate that differences in the impact of GH on longevity in mice versus people stem from major differences in life history, energy partitioning, and reproductive strategy between species with a different pace-of-life. The slow pace-of-life of humans combined with the impacts of social organization, public health measures, and medical advances, favors longevity and makes it difficult to induce further increase in lifespan.

Prevalence of Cellular Senescence May Explain the Inverse Correlation Between Cancer and Neurodegeneration
https://www.fightaging.org/archives/2021/03/prevalence-of-cellular-senescence-may-explain-the-inverse-correlation-between-cancer-and-neurodegeneration/

One of the more curious aspects of aging is that risk of Alzheimer's disease and risk of cancer is inversely correlated. Why is this the case? Researchers here suggest that cellular senescence may be an important component of this relationship. If cells in a given individual are more than averagely prone to becoming senescent in response to stress and damage, then this may lower the risk of cancer, as precancerous cells will be blocked from replication and removed by the immune system more efficiently. On the other hand, increased cellular senescence in the aging brain will more rapidly drive chronic inflammation and neurological dysfunction, leading to an increased risk of dementia.

Given this, we are fortunately to live in an era in which senolytic drugs to selectively remove senescent cells now exist. Some of them, such as the combination of dasatinib and quercetin, can bypass the blood-brain barrier to destroy senescent cells in brain tissue. This therapy has been shown to reduce chronic inflammation and reverse Alzheimer's pathology in mouse models of the condition. Human trials in Alzheimer's patients are somewhere in the early stages of organization, and we can hope that this strategy will outperform past efforts.

Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells-Implications for Cancer and Neurodegeneration

The risk of both neurodegenerative disease and cancer increases with advanced age due to increased damage accumulation and decreased repair capabilities; yet the relative odds of developing one or the other are inversely correlated. Molecular profiling studies have identified disrupted genes, proteins, and signaling pathways shared by neurodegenerative diseases and cancer, but in opposing directions. For example, p53 is upregulated in Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, but downregulated in many cancers. Similarly, mutations of the Parkin gene (PARK2) have been shown to simultaneously contribute both to Parkinson's disease and tumor suppression. A recent study performed transcriptomic analyses of four different tissues from four different species at ages across their lifespan. Across samples, the largest number of shared risk single nucleotide polymorphisms (SNPs) were in the genomic locus containing the long non-coding RNA ANRIL which modulates many cell cycle regulators including CDKN2A/B, which codes for p16INK4A (hereon referred to as p16), one of the best characterized mediators of cellular senescence. Notably, SNPs in this locus were identified in the brain, as well as other tissues analyzed. These results point toward aberrant cell cycle, and in particular senescence, as a key age-associated molecular pathway worth further study.

Cellular senescence has emerged as a hallmark biological process that promotes aging. The pillars of aging, including cellular senescence, are highly interconnected and do not occur in isolation. For example, epigenetic changes, telomere attrition, DNA damage, and mitochondrial dysfunction all may induce cellular senescence, which then contributes to dysfunctional nutrient signaling and proteostasis. Consequences of cellular senescence include stem cell exhaustion and chronic inflammation. Thus, cellular senescence represents an intersection of aging hallmarks. While best studied as an anti-cancer stress response, recent studies highlight its pro-degenerative role in AD and tauopathies. As such, cellular senescence may contribute to the inverse correlation between the risk for developing neurodegeneration and that for cancer.

Bulk tissue analyses, while informative at a macroscopic level, may not capture important changes occurring in single cells. Senescent cell abundance increases with aging, but the relative contribution to a tissue is relatively low and may be missed in bulk analyses. Several laboratories are using single cell technologies to assign cell type specificity to tissue-level observations, but to date these analyses have not included senescent cells in the brain. To maximize generalization and interpretation across studies, in this review we only evaluate studies which investigated cellular senescence with cell type specificity, and not bulk analyses. The present compilation provides evidence on conditions in which cellular senescence may benefit (anti-cancer) or negatively impact (neurodegeneration) brain health. In doing so, this review explores how the cellular senescence stress response may simultaneously distinguish and connect AD and cancer risk.

Flies that Choose a Poor Diet Have a Shorter Lifespan than those Forced into a Poor Diet
https://www.fightaging.org/archives/2021/03/flies-that-choose-a-poor-diet-have-a-shorter-lifespan-than-those-forced-into-a-poor-diet/

This interesting study shows that when given the choice to consume sugar or protein, flies consume a lot of sugar and exhibit reduced life span as a result. Feeding the same proportional mix of sugar and protein to flies without giving them the choice of what to consume does not reduce life span to the same degree, however. The researchers have identified a specific signaling pathway that is responsible for this outcome, involved in the neuronal regulation of metabolism, a part of the only partially explored feedback loop between diet and appetite. This is all fascinating, but it is hard to say whether it has any near term relevance to health in humans.

What constitutes a good diet remains a matter of continuous debate. The typical way of addressing such questions in a laboratory setting would be to compare groups given diets with different macronutrient compositions and measure their lifespans. But in real life, food is neither presented nor consumed that way. First, foods vary in their composition of macronutrients. Second, all creatures tend to have innate preferences towards certain foods. Taking these discrepancies into account, would we see a connection between macronutrients and longevity in a more naturalistic, choice-based food environment?

Researchers set out to address this topic in a widely used model system, the fruit fly Drosophila melanogaster. In the first set of experiments, one group of wild-type fruit flies spent their lives on a diet consisting of equal amounts of sugar and protein (fixed diet). The second group received the same amount and ratio of sugar and protein, but they could choose between the two foods (choice diet). Then, the amount of food consumed and lifespans were measured and compared across both groups. Alas - and perhaps unsurprisingly - flies given the choice between sugar and protein consumed far more sugar and lived less long than those given no choice in the matter.

However, the reduced longevity of the 'sweet-toothed' flies could not be attributed solely to sugar-induced toxicity. Even flies given up to three times as much sugar as protein in the fixed-diet group had an intermediate lifespan. Additionally, other measures, such as intestinal permeability and locomotion, were unaltered by the choice diet, at least in young flies. Not even a major messenger molecule in the insulin signaling pathway (dFOXO), a key culprit in diet-induced longevity, was greatly affected by a choice-driven diet. Instead, it appeared that being presented with the choice itself led to increased sugar consumption and reduced longevity.

Researchers were able to show that a serotonin receptor called 5HT2A was responsible for the choice-induced reduction in lifespan. However, when 5HT2A was removed, flies on a choice diet no longer had shortened lifespans, even though they consumed just as much sugar as the wild-type flies. Researchers suspected that variations in internal nutrients could be behind the observed changes in lifespan. They compared a large number of metabolites relevant for converting food to energy in flies raised on both diets, and with or without 5HT2A. Over 80% of these metabolites did not change. However, in flies raised on a choice-diet, four amino acids (lysine, glutamine, asparagine, and aspartate) increased in a 5HT2A-dependent manner.

Prevalence of Ischemic Scars in the Retina Correlates with Heart Disease Risk
https://www.fightaging.org/archives/2021/03/prevalence-of-ischemic-scars-in-the-retina-correlates-with-heart-disease-risk/

Researchers here note that the visible signs of vascular degeneration in the retina correlate with the risk of cardiovascular disease. The worse the state of the retina, the more likely it is that a patient will develop cardiovascular disease. Similar degenerative processes are at work throughout the vasculature, but the location of the retina allows for a cost-effective visual inspection of blood vessels using established tools.

Researchers have identified a potential new marker that shows cardiovascular disease may be present in a patient using an optical coherence tomography (OCT) scan - a non-invasive diagnostic tool commonly used in ophthalmology and optometry clinics to create images of the retina. The finding suggests it may be possible to detect heart disease during an eye examination. The research team examined lesions of the retina, the inner-most, light-sensitive layer of the eye, to determine if a cardiovascular disorder may be present.

"The eyes are a window into our health, and many diseases can manifest in the eye; cardiovascular disease is no exception. Ischemia, which is decreased blood flow caused by heart disease, can lead to inadequate blood flow to the eye and may cause cells in the retina to die, leaving behind a permanent mark. We termed this mark 'retinal ischemic perivascular lesions,' or RIPLs, and sought to determine if this finding could serve as a biomarker for cardiovascular disease."

As part of the study, the team reviewed the records of individuals who received a retinal OCT scan. From that cohort, two groups were identified after medical chart review: one consisted of 84 individuals with heart disease and the other included 76 healthy individuals as the study's control group. An increased number of RIPLs was observed in the eyes of individuals with heart disease. According to the researchers, the higher number of RIPLs in the eye, the higher the risk for cardiovascular disease. Detection of RIPLs could result in identification of cardiovascular disease that would enable early therapy and preventative measures, and potentially reduce numbers of heart attacks or strokes.

Immunoglobulin-M Antibodies Reduce Risk of Thrombosis by Binding to Extracellular Vesicles that Induce Coagulation
https://www.fightaging.org/archives/2021/03/immunoglobulin-m-antibodies-reduce-risk-of-thrombosis-by-binding-to-extracellular-vesicles-that-induce-coagulation/

Researchers have in the past found that low levels of immunoglobulin-M antibodies correlate with an increased risk of thrombosis, the blockage of a blood vessel by, for example, fragments of a ruptured atherosclerotic plaque. Here, more details regarding this relationship are reported, suggesting that therapies designed to increase immunoglobulin-M antibody levels could be useful in reducing the incidence of heart attack and stroke resulting from thrombosis.

Antibodies are an important component of the immune system. On the one hand, these proteins serve in the body to defend against microbes, and on the other hand to remove the body's own "cell waste". Naturally occurring antibodies which are present from birth and mostly of the immunoglobulin-M (IgM) type, play an essential role in these processes. In the context of thrombosis, earlier studies demonstrated that people with a low number of IgM antibodies have an increased risk of thrombosis. Thrombotic occlusion of blood vessels, which leads to myocardial infarctions, strokes, and venous thromboembolisms, is the major cause of death in the western hemisphere. Therefore, it is of critical importance to understand the mechanisms that might prevent thrombus formation.

Microvesicles, blebs shed from the membrane of cells, are critical mediators of blood coagulation and thrombus formation. Researchers have now demonstrated that natural IgM antibodies that bind oxidation-specific epitopes can prevent coagulation and thrombosis induced by microvesicles. This provides a mechanistic explanation for the previously published observation that low levels of these antibodies are associated with an increased risk of thrombosis. Both in experiments on a mouse model and directly on human blood samples, the scientists were able to show that the addition of IgM antibodies inhibited blood clotting caused by specific microvesicles and protected mice from lung thrombosis. Conversely, it was also shown that depletion of the IgM antibodies increased blood clotting.

"The results offer high potential for novel treatments to reduce the risk of thrombosis. Influencing IgM antibody levels in high-risk patients could be a viable addition to the previously established blood thinning treatment, as this is also known to be associated with side effects such as an increased tendency to bleed in the case of injuries."

The Popular Science Media Fails to Distinguish Between Potentially High Yield and Probably Low Yield Treatments for Aging
https://www.fightaging.org/archives/2021/03/the-popular-science-media-fails-to-distinguish-between-potentially-high-yield-and-probably-low-yield-treatments-for-aging/

It is of great importance to distinguish, where we can, between promising and poor approaches to the treatment of aging. If only poor approaches are developed, then we'll age, suffer, and die on much the same schedule as our grandparents. In the article here, metformin and senolytics are crammed together side by side, as though the same thing. They are very much not the same thing.

Metformin is almost certainly a poor approach to the treatment of aging. The animal data is terrible, while the human data shows only a modest effect size. Senolytics are most likely a promising approach. The animal data is amazing: robust, reliable rejuvenation and reversal of many currently untreatable age-related diseases via any approach that removes a third or more of the senescent cells that linger in old tissues. The degree to which this is going to do great things in people remains to be determined. But it is fair to wager that it will be a good deal better than the results to date from metformin. If we're going to spend extensive time and funding on something, why the obviously worse option? Why aim so low?

In recent years, many experts in the aging field have come to believe that certain medications acting at the cellular and metabolic level can slow aging by staving off its most striking effects - frailty and ­age-related diseases, for example - and extend healthy life in doing so. Now they are setting out to prove it. "We're not about the fountain of youth," says Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine. "That's taking an old person and making him young. What we are saying is that we can delay aging."

Drugs with the ability to postpone or prevent the onset of debilitating diseases could lead to additional healthier years, enhancing longevity and providing enormous societal benefits, experts say. Leading the list of candidates is metformin, a longtime treatment for type 2 diabetes, and rapamycin, a chemotherapy agent and immunosuppressant. Scientists also are studying a class of compounds known as senolytics, which attack "senescent" cells in the body that tend to proliferate with age. Senescent cells damage healthy cells around them, contributing to multiple age-related diseases.

But such drugs could face a daunting challenge, since aging is not considered a disease. This means the Food and Drug Administration is unlikely to approve a drug for its anti-aging effects, or as a new use for a licensed drug. Also, pharmaceutical companies probably wouldn't be inclined to develop drugs for that purpose only. Scientists hope to circumvent that hurdle by conducting a study - in this case, with metformin - to test whether it can prevent or delay three age-related diseases - dementia, heart disease and cancer - and, in doing so, extend life.

At least one study had heightened their interest in the drug as possibly life-extending after researchers noticed that diabetics who took the drug outlived non-diabetics who did not. Moreover, metformin had shown an effect in separate studies against each of the three diseases, prompting the researchers to try to put all the pieces together in one large randomized controlled clinical trial. The result is a proposed six-year clinical trial, known as Targeting Aging With Metformin (TAME), which will recruit 3,000 subjects ages 65 to 79 at 14 research sites. In testing whether metformin can prevent or delay the three diseases, researchers also hope to learn whether this results in those taking metformin outliving those not taking the drug, thus extending healthy life. (One reason for choosing metformin was because of its long track record, safety, and inexpensive cost.)

"The goal is not to help people live forever, but help them stay healthy longer," says Steven Austad, who chairs the biology department at the University of Alabama at Birmingham and is senior scientific director of the American Federation for Aging Research. "But the fringe benefit is that you live longer."

Raised Levels of Amyloid-β in the Retina Impair Lysosomal Function
https://www.fightaging.org/archives/2021/03/raised-levels-of-amyloid-%ce%b2-in-the-retina-impair-lysosomal-function/

Lysosomes recycle unwanted and damaged molecules in the cell, and are thus vital to cell health. Unfortunately, lysosomal function is progressively impaired with age. This occurs as a result of the buildup of various persistent metabolic byproducts, particularly in long-lived cells such as those of the central nervous system. Much of the research on this topic is focused on the impact of lipofuscin, but, as noted in the materials here, other forms of metabolic waste can also negatively impact lysosomal function. This loss of function contributes to age-related conditions, such as the retinal degeneration discussed here.

Amyloid beta (Ab) proteins are the primary driver of Alzheimer's disease but also begin to collect in the retina as people get older. Donor eyes from patients who suffered from age-related macular degeneration (AMD), the most common cause of blindness amongst adults in the UK, have been shown to contain high levels of Ab in their retinas.

A new study builds on previous research which shows that Ab collects around a cell layer called the retinal pigment epithelium (RPE), to establish what damage these toxic proteins cause RPE cells. The research team exposed RPE cells of normal mouse eyes and in culture to Ab. The mouse model enabled the team to look at the effect the protein has in living eye tissue, using non-invasive imaging techniques that are used in ophthalmology clinics. Their findings showed that the mouse eyes developed retinal pathology that was strikingly similar to AMD in humans.

The investigators also used the cell models, which further reduced the use of mice in these experiments, to show that the toxic Ab proteins entered RPE cells and rapidly collected in lysosomes, the waste disposal system for the cells. Whilst the cells performed their usual function of increasing enzymes within lysosomes to break down this unwanted cargo, the study found that around 85% of Ab still remained within lysosomes, meaning that over time the toxic molecules would continue to accumulate inside RPE cells. Furthermore, the researchers discovered that once lysosomes had been invaded by Ab, around 20 percent fewer lysosomes were available to breakdown photoreceptor outer segments, a role they routinely perform as part of the daily visual cycle.

Estimating that Technological Progress Accounts for Half of the Gains in Life Span Since the 1960s
https://www.fightaging.org/archives/2021/03/estimating-that-technological-progress-accounts-for-half-of-the-gains-in-life-span-since-the-1960s/

Researchers here build an economic model of technological progress and its impact on human life span. The model suggests that advances in technology account for half of the gains in life span from the 1960s on. This is in much the same ballpark as other initiatives that have asked similar questions regarding the causes of the slow upward trend in human longevity over the past century or more.

Life expectancy at birth is presently increasing at something like two years per decade, while remaining life expectancy at 65 is increasing at one year per decade. We should expect this trend to leap upward as the first rejuvenation therapies to deliberately target the mechanisms of aging enter widespread use. Past gains were achieved almost accidentally, as no meaningful efforts were made at the time to directly address the causes of aging. That state of affairs has now changed, and we should expect better outcomes as a result.

We estimate a stochastic life-cycle model of endogenous health spending, asset accumulation, and retirement to investigate the causes behind the increase in health spending and longevity in the United States over the period 1965-2005. Accounting for changes over time in taxes, transfers, Social Security, income, health insurance, smoking and obesity, and technological progress, we estimate that technological progress is responsible for half of the increase in life expectancy over the period.

Substantial growth in health spending over the period is largely the result of growth in economic resources and the generosity of health insurance, with a modest role for medical technological progress. The growth in spending does not come from changes in a single source, but sources jointly interacted to increase spending: complementarity effects explain up to 26.3% of the increase in health spending. Overall, for those born in 1940, the combined changes in resources and health insurance that occurred over the period are valued at 35.7% of lifetime consumption.

Thoughts on Medical Progress and Living Longer
https://www.fightaging.org/archives/2021/03/thoughts-on-medical-progress-and-living-longer/

This article expresses sentiments regarding medical technology and human longevity that we'd all like to see more of in the mainstream media. At some point, it will come to be seen by the average person as basically sensible to work towards minimizing the tide of suffering and death caused aging and age-related disease. It has been, in hindsight, a strange thing to live in a world in which most people were reflexively opposed to that goal.

Death and aging constitute a mystery. Some of us die more quickly. We often ask about it as children, deny it in youth, and reluctantly come to accept it as adults. Aging is universal across all species. In the bare-fact of our aging and dying, we resemble all other animals; in the details, however, we've improved considerably over the course of our history. At some point, our bodies decide to grow senescent and then to die. It's intrinsic, initiated from within the organism. The repeated shuffling of sirtuins and other epigenetic factors away from genes to sites of broken DNA, then back again (while helpful in the short term) is ultimately what causes us to age. Over time the wrong genes come on at the wrong time and in the wrong place. When you disrupt the epigenome by dealing with DNA breaks, it results in an erosion of the epigenetic landscape of misguided and malfunctioning cells.

A malady that impacts less than half the population is a 'disease'. Aging impacts everyone and therefore is an inevitable, irreversible decline in organ function that occurs over time even in the absence of injury, illness, environmental risks, or poor lifestyle choices. Aging limits the quality of life and has a specific pathology. It does all this and in doing so it fulfills every category of what we call a 'disease', except one; it impacts more than half of the population. It's the mother of all diseases, the one we all suffer from. Aging, by all means, is a disease though not yet considered so by any country. Insurance companies don't cover pharmaceuticals to treat cases that aren't recognized by government regulators even if it benefits humanity and the nation's bottom line. Without such a designation, unless you're suffering from a specific disease, longevity drugs will have to be paid for out of pockets, for they'll be elective luxuries.

As nobody has been working on any cure, because what's wrong with oldies isn't viewed as an illness. It's thought to be an inevitable part of life. Cancer, heart diseases, Alzheimer's, and other conditions we commonly associate with getting old aren't necessarily diseases themselves but symptoms of something greater. Efforts to define aging as a 'disease' both in custom and on paper will change the course of the future. Besides public funding to augment the cure doctors will feel comfortable prescribing medicines, such as Metformin, to their patients before they become irreversibly frail. Jobs will be created and scientists and drug makers will flock, industries will flourish.

There's a difference between extending life and prolonging vitality. We're capable of both but simply keeping people alive is no virtue. Life-extension means the recovery of the physical/intellectual capital that's tied up in hospitals and clinics, treating sick oldies. Add to this the billions of additional women, if provided, much longer windows of opportunity for pregnancy and parenting and extended female fertility by up to a decade or so. Imagine the combined intellectual power of the men and women who're currently sidelined due to age-discrimination, socially enforced ideas about the right time to retire, and diseases that rob them of the physical and intellectual capacity to engage, as they once did.

Improving Autophagy to Restore Hematopoietic Function in Aged Individuals
https://www.fightaging.org/archives/2021/03/improving-autophagy-to-restore-hematopoietic-function-in-aged-individuals/

Upregulation of LAMP2A is capable of improving the operation of chaperone-mediated autophagy in later life. A while back researchers demonstrated meaningfully improved liver function in mice via this mechanism. Here, they start from the same point of LAMP2A and autophagy in order to try to address the age-related faltering of the hematopoietic system responsible for producing red blood cells and immune cells. With age hematopoietic stem cells become damaged and change their behavior in ways that degrade immune function, such as be producing too many myeloid cells and too few lymphoid cells. Can this be addressed to some degree by upregulation of chaperone-mediated autophagy? The evidence is suggestive.

Creating 200 billion-plus brand-new red blood cells a day can take a toll on a body. The capacity to replace components charged with the life-sustaining task of carrying oxygen eventually wears out with aging, resulting in health problems, from anemia to blood cancers. What if we could halt the aging process and maintain young blood cells for life? With blood cells making up a whopping 90% of the body's cells, it makes sense that keeping them abundant and fit could boost vitality into our golden years.

Blood cells are responsible for oxygen transport, infection control, and many other things scientists are just discovering. But they have a short lifespan - 120 days for red blood cells, and even shorter for other blood cells - and must regenerate continuously throughout life, he said. "This fascinating phenomenon is made possible by the capacity of hematopoietic stem cells (HSCs) to multiply and differentiate into all the blood cell types, a mechanism that unfortunately can become impaired as we get old. Results can include anemia, when we can't make enough red blood cells, or blood cancers, when some blood cell precursors go rogue and start multiplying without differentiating,"

The researchers targeted chaperone-mediated autophagy (CMA), one mechanism they found responsible for the degradation. Like a housekeeper gone awry, CMA with age can fail in its job of cleaning up damaged proteins and other wastes, sabotaging the HSCs' capacity to make new, healthy blood cells. Pinpointing one key protein (LAMP2A) that regulates CMA function whose expression and activity declines with age, the scientists used both genetic, dietary and pharmacological interventions that restored young hematopoiesis (formation of blood cellular components) in old laboratory mice.

The scientists also showed that a metabolic enzyme (FADS2) involved in fatty acid metabolism loses function with age, reducing healthy blood cell formation. By introducing gamma linolenic acid (GLA), a product of the failing enzyme, in the rodents' diets, the researchers again improved cell regeneration. After determining that the CMA dysfunctions in mice mirrored those in 70-plus-year-old humans, the researchers believe their findings could eventually translate into reversing the aging process of HSCs in humans, opening the door to numerous medical therapies.

SPACs for Longevity Companies: Helpful or Not?
https://www.fightaging.org/archives/2021/03/spacs-for-longevity-companies-helpful-or-not/

The present popularity of SPACs, special purpose acquisition companies, might be cynically thought of as being a sign that quantitative easing is catching up with us - there is too much money sloshing around in the system, all of it chasing too few opportunities for significant returns. A SPAC is a publicly traded shell company that accepts investment prior to any specific idea as to what exactly the funds will be used for, sets a few famous people as figureheads to drum up interest, and then buys established companies or sizable stakes in established companies. It is something of the reverse of the more traditional route to taking companies public. There will be SPACs for the longevity industry, because the longevity industry is a hot topic right now.

Will this help, in the sense of will it accelerate the path to widely available therapies that can meaningfully impact the course of aging? The argument for: there is still a dearth of funding for later stage longevity-focused companies, and it is harder than it should be to obtain the funds needed to make the transition from preclinical to clinical development in this space. The argument against: the clinical development funding gap isn't the real problem, which is instead that the right programs (i.e. an implementation of all of the component parts of the SENS agenda for human rejuvenation) are still not being funded at the research and seed stage in large enough numbers. Those programs will, on balance, achieve sizable enough results in animal studies to have no challenge in pulling in later funding.

Frontier Acquisition Corporation, a special purpose acquisition company formed for the purpose of entering into a combination with one or more biotech businesses, has announced the pricing of its initial public offering of 200 million. Interestingly, the line-up includes Co-Chairmen Peter Attia, a practising physician focusing on the applied science of longevity, and David Sinclair, Professor of Genetics at Harvard Medical School and co-founder of several biotechnology companies.

The new company is headed by German investor Christian Angermayer, founder of Apeiron Investment Group and Chairman and Co-Founder of Cambrian Biopharma. Angermayer laid out his views last year in a detailed post on LinkedIn, where he stated, "Put simply, I want to live forever! And in perfect health! And it is my sincere belief that we will achieve the means to do this within the next 20-30 years."

Angermayer is a serial entrepreneur, backing about 30 life sciences companies, including Atai Life Sciences, Sensei Biotherapeutics, Compass Pathways, and Abcellera. In a statement he said, "I deeply believe biotechnology will be one of the best asset classes to invest in over the next decade. We will see incredible progress that we so far didn't dare to dream about."

Mitochondrial Transplantation as a Treatment for Heart Disease
https://www.fightaging.org/archives/2021/03/mitochondrial-transplantation-as-a-treatment-for-heart-disease/

Mitochondria are the power plants of the cell, generating the chemical energy store molecule ATP. The function of mitochondria declines throughout the body with age, and this is particularly impactful in energy-hungry tissues such as the heart. This decline appears to involve changes in mitochondrial shape and dynamics, as well as failing mitophagy, the quality control mechanism responsible for removing worn and damaged mitochondria. This is all clearly the end of a chain of cause and effect involving many other processes, starting with the root causes of aging, and passing through altered epigenetic regulation and expression of necessary proteins.

One possible approach to therapy is to bypass all of the unknowns and transplant functional mitochondria into the patient in large numbers. These are taken up by cells and put to work. This has been shown to produce benefits in animal models, and a few human clinical studies have taken place, but is nonetheless still a form of therapy in the comparatively early stages. There are plenty of unanswered questions, such as how large a fraction of the native mitochondria can be replaced safely at any one time, how long the benefits last before new mitochondria succumb to the aged cellular environment, and whether long-term complications can arise when a different mitochondrial genome is introduced. Still, it is quite an exciting area of development: we should start to see firm answers to these questions over the next decade or so.

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the "stem-less" approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of microRNAs or by modifying the cellular energy metabolism via targeting mitochondria.

Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations.

Despite previous promising usage of mitochondria for transplantations, important considerations regarding the significant aging effects of somatic cells, stem cells, and mitochondria as well as factors like safety issues, tissue sources, and possible disease effects deserve further investigations when mitochondrial transplantations are to be used for future applications. Factors influencing stem cell and mitochondria function include age of the cells, probably previous divisions of the cells, heterogeneity of stem cells as well as mitochondria, and likely tissue source and additional diseases. Furthermore after the first positive reports, the time of treatment for the most beneficial effect and repetitions of applications should be further investigated: positive effects have been shown pre ischemia, prior to and during reperfusion as well as after delayed application.

The quantity of mitochondria seems to be less critical as only a small number of mitochondria is needed for improving cardiac functions. The development of further safety and storage solutions for mitochondria could improve applications. Following the first promising reports of stem cell derived mitochondria further research especially considering the differences of autologous (maybe collection in early life stages and asservation for later use) vs. allogeneic vs. syngeneic sources deserve further investigations and will surely lead to exiting new developments during the upcoming years.