Fight Aging! Newsletter, September 13th 2021

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  • Successfully Treating Fibrosis in Mice via the Senolytic Strategy of Bcl-2 Inhibition
  • A Brief Tour of Work on Reprogramming as an Approach to the Treatment of Aging
  • A Study of Nattokinase Supplementation Shows No Effect on Progression of Atherosclerosis
  • The Evolutionary Layering of the Mechanisms of Aging
  • Dendritic Cells Migrate to the Thymus to Cause Slow Thymic Involution Over a Lifetime
  • How Much of Cardiovascular Disease is Self-Inflicted?
  • Altos Labs Formed to Work on the Treatment of Aging
  • More Blood Pressure Control is Better than Less Blood Pressure Control
  • Correlations Between p53 Sequence Differences and Species Lifespan
  • ILC2 Immune Cells Become Altered with Age in Ways that Impair Thermoregulation
  • Questioning the Reproducibility of Fly Life Span Studies
  • Quantifying the Effects of a Five Day Fast for Comparison with Fasting Mimicking and Calorie Restriction
  • Protection versus Harm: Cellular Senescence in the Context of Cancer
  • Mitochondrial-Derived Peptides as Targets for Cardiovascular Disease Therapies
  • Impetus Grants for Longevity Research

Successfully Treating Fibrosis in Mice via the Senolytic Strategy of Bcl-2 Inhibition

It has to be said, today's research materials make for a fascinating read. A group of scientists, in 2021, a decade into the general acceptance of the importance of cellular senescence as a phenomenon, conducts a study of lung fibrosis in which they achieve a reversal of that fibrosis using a bcl-2 inhibitor, venetoclax, and then publish a paper that fails to mention cellular senescence even once.

Fibrosis is a dysfunction of tissue maintenance, producing scar-like collagen deposits that disrupt tissue function. There is a weight of evidence for fibrosis as a phenomenon to be driven by the presence of senescent cells, including the use of various senolytic therapies in animal studies to reverse fibrosis. Initial human trials for one of those senolytic therapies are ongoing, and one of those trials was an attempt to treat lung fibrosis.

Many of the senolytic therapies established in animal studies are bcl-2 inhibitors, such as navitoclax, a close relative of venetoclax. Inhibition of BCL2 family proteins has the effect of driving senescent cells into self-destruction, reducing their resistance of programmed cell death stimuli. This was the one of the first approaches to the selective destruction of senescent cells to be validated in the laboratory, and is widely studied and appreciated in the research community.

So it is to my eyes a little odd for a research group to run a study using a senolytic drug, targeting a well-known apoptosis-related pathway, on a condition that is generally acknowledged to involve senescent cells, and then focus on everything other than senescence as a possible mechanism. Not even a mention in the discussion section. The exploration of bcl-2 in macrophages in the lung is certainly interesting, as macrophages are likely involved in everything that touches upon tissue maintenance, including fibrosis, but without addressing cellular senescence in some way it is hard to take the conclusions at face value here.

Reversal of lung fibrosis in mouse model suggests a novel therapeutic target for pulmonary fibrosis

Mice were given bleomycin for 12 days to establish lung fibrosis, and then treated daily until 21 days with ABT-199, whose medical form is known as Venetoclax, a medication approved by the FDA for use in several forms of leukemia. Control bleomycin mice had lung fibrosis with widespread collagen deposition. The bleomycin mice that received ABT-199 had normal lung architecture at 21 days and no collagen deposition.

Pulmonary fibrosis is a chronic disease showing aberrant remodeling of lung tissue. Idiopathic pulmonary fibrosis is the most common form of pulmonary fibrosis and has a high mortality rate within three to five years. Currently approved medications have limited efficacy. ABT-199 acts by inducing apoptosis, or programmed cell death, in monocyte-derived macrophages in the lung. Macrophages are large white blood cells that engulf and digest anything that does not have the surface proteins of healthy cells. Targets can include cancer cells, microbes, and cellular debris.

Researchers isolated macrophages from people with IPF. They found a marked increase in the macrophage mitochondrial protein Bcl-2 - a regulator of apoptosis - as compared to lung macrophages from people without IPF. Mitochondrial Bcl-2 was also elevated in lung macrophages from bleomycin-exposed mice that have lung fibrosis. Researchers found that mice with a conditional deletion of Bcl-2 in lung macrophages were protected from pulmonary fibrosis in the bleomycin model, and they were also protected from asbestos-induced lung fibrosis. These conditional deletion results set the stage for the experiments showing that the Bcl-2 inhibitor ABT-199 was able to reverse fibrosis in the mouse bleomycin model.

Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling

Fibrosis progression is associated with apoptosis resistance in lung macrophages; however, the mechanism by which apoptosis resistance occurs is poorly understood. Here, we found a marked increase in mitochondrial B-cell lymphoma-2 (Bcl-2) in lung macrophages from subjects with idiopathic pulmonary fibrosis (IPF). Similar findings were seen in bleomycin-injured wild-type (WT) mice, whereas Bcl-2 was markedly decreased in mice expressing a dominant-negative mitochondrial calcium uniporter (DN-MCU). Carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme for fatty acid β-oxidation, directly interacted with Bcl-2 by binding to its BH3 domain, which anchored Bcl-2 in the mitochondria to attenuate apoptosis. This interaction was dependent on Cpt1a activity.

Lung macrophages from IPF subjects had a direct correlation between CPT1A and Bcl-2, whereas the absence of binding induced apoptosis. The deletion of Bcl-2 in macrophages protected mice from developing pulmonary fibrosis. Moreover, mice had resolution of fibrosis when Bcl-2 was deleted or was inhibited with ABT-199 (venetoclax) after fibrosis was established. These observations implicate an interplay between macrophage fatty acid β-oxidation, apoptosis resistance, and dysregulated fibrotic remodeling.

A Brief Tour of Work on Reprogramming as an Approach to the Treatment of Aging

A recent popular science article from the team provides a high level introduction to cellular reprogramming as a potential approach to the treatment of aging. Since the discovery that somatic cells can be reprogrammed to become induced pluripotent stem cells, essentially the same as embryonic stem cells, most exploration has focused on the cost-effective production of specific cell types for use in research and cell therapies. More recently, however, researchers have applied reprogramming strategies directly to tissues in living animals in order to improve heath and turn back aspects of aging and age-related disease.

Reprogramming is achieved by inducing expression of a few or all of the Yamanaka factors, genes regulating pluripotency. Scientists have observed that reprogramming of cells from old tissues reverses age-related epigenetic marks, gene expression changes, and mitochondrial dysfunction. It is a process that recapitulates some of the rejuvenation that takes place in early embryonic development, as cells clear out molecular damage and reset themselves for the task of building an embryo. Some studies have shown that delivering reprogramming factors into adult animals as a therapy produces benefits to health and signs of reversal of age-related pathology. There are clearly safety concerns in taking this approach to therapy, in that the production of even small numbers of pluripotent cells can lead to cancer, even as those cells improve tissue function via their signaling, in much the same way as the transplanted cells of first generation stem cell therapies. It isn't just a matter of producing a sort of in situ stem cell therapy, however; somatic cells exposed to lesser amounts of reprogramming factors can exhibit improved function without transforming into stem cells.

Reprogramming is not an instant event, not a switch. It is a process of change that requires sustained expression of reprogramming factors over some period of time, typically days. Shorter, lesser exposure to reprogramming factors can improve cell function by reversing age-related epigenetic changes and mitochondrial dysfunction without resulting in a transformation of cell type. This useful outcome of partial reprogramming may or may not prove to be challenging to reliably and safely achieve in living tissues. Different cell types require different timing, different recipes for effective reprogramming, and every aging organ in the body is made up of many different cell types. This is a work in progress.

Yamanaka Factors and Making Old Cells Young

In 2006, a study showed that it was possible to reprogram cells using just four master genes named Oct4, Sox2, Klf4, and c-Myc, or OSKM for short. These four reprogramming factors are often called the Yamanaka factors. This discovery paved the way for research into how these Yamanaka factors might be used for cellular rejuvenation and a potential way to combat age-related diseases. In 2011, a team first reported cellular rejuvenation using the Yamanaka factors. During their life, cells express different patterns of genes, and those patterns are unique to each phase in a cell's life from young to old; this gene expression profile makes it easy to identify an old or young cell.

In 2016, researchers showed for the first time that the cells and organs of a living animal could be rejuvenated via reprogramming. For the study, the researchers used a progeric mouse designed to age more rapidly than normal as well as a normally aging mouse strain. Both types of mice were engineered to express the Yamanaka factors when they came into contact with the antibiotic doxycycline, which was given to them via their drinking water. After just six weeks of this treatment, which steadily reprogrammed the cells of the mice, the researchers noticed improvements in their appearance, including reduced age-related spinal curvature. The treated mice also experienced a 50% increase in their mean survival time in comparison to untreated progeric control mice. It should be noted that not all aging signs were affected by partial cellular reprogramming, and if treatment was halted, the aging signs returned.

In 2020, another study howed that partial cellular reprogramming improves memory in old mice. As the previous studies have shown, partial cellular reprogramming is a balancing act between epigenetically rejuvenating cells and resetting their aging clocks, without completely resetting their cell identity so they forget what kind of cell they are. Also in 2020, researchers published a study that showed that they had managed to restore lost vision to old mice, and mice with damaged retinal nerves, using partial cellular reprogramming.

By far the biggest hurdle to translating partial cellular reprogramming to people is the need to find a way to activate the Yamanaka factors in our cells without needing to engineer our bodies to react to a drug such as doxycycline. Doing this may require us to develop drugs capable of activating OSKM, editing every cell in our body to respond to a particular compound like doxycycline, which would be extremely challenging though plausible. The rapid progress of medical technology could potentially mean that such partial cellular reprogramming therapies may become available in the not too distant future. We certainly hope so.

A Study of Nattokinase Supplementation Shows No Effect on Progression of Atherosclerosis

You might recall a Chinese study from a few years back claiming a sizable effect on atherosclerotic plaque for supplementation with nattokinase. The result was a 36% reversal in plaque size, which is several times larger than can be reliably achieved with approaches such as statins and their successors, drugs that lower blood cholesterol. The dose was 6000FU/day for 6 months. My attention was recently drawn to the publication of results for a US study using dose of 2000FU/day for several years. In that study, there was no effect on the progression of atherosclerosis, and certainly no marked reversal.

Medicine in general has a serious replication issue, in that all too many claimed results evaporate when a more rigorous study is undertaken. One only has to look at the NIA Interventions Testing Program to see many claims of longer mouse life spans refuted by more careful work. Problems with replication and study quality are particularly the case for clinical work conducted outside the US and Western Europe. One can find a great many researchers in wealthier nations who are immediately and reflexively skeptical of studies in their field that were conducted in other parts of the world.

That aside, is this a question of different doses and patients with a different severity of disease? Perhaps, but when one sees data with this sort of inconsistency, it casts doubt on whether there is or can be an effect size large enough to be interesting. Nattokinase does appear to have an effect on mammalian biochemistry and cell behavior that could influence atherosclerosis, but that is never the point. Mechanisms are what they are, the question is always whether or not the effect size of manipulating the mechanism in this way, with this treatment, is large enough to pursue.

Nattokinase atherothrombotic prevention study: A randomized controlled trial

Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units (FU) daily or matching placebo. The primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers.

After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. The results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Nattokinase Atherothrombotic Prevention Study (NAPS)

The potential for nattokinase to "thin" blood and to reduce blood clotting by positive antithrombotic and fibrinolytic effects presents a unique opportunity to safely study such effects on cardiovascular disease and cognition. Using nattokinase under primary prevention conditions, the investigators propose to conduct a randomized, double-blinded, placebo-controlled trial to determine whether decreasing atherothrombotic risk can reduce the progression of atherosclerosis and cognitive decline. The investigators propose to randomize 240 healthy non-demented women and men to nattokinase supplementation or to placebo for three years. The primary trial endpoints will be measurement of carotid arterial wall thickness and arterial stiffness, early changes of atherosclerosis that can be measured safely by non-invasive imaging techniques.

At the conclusion of this trial, the investigators expect to have sufficient evidence as to whether reducing the propensity for thrombus formation and/or increasing fibrinolytic activity can prevent the progression of atherosclerosis and cognitive decline. These results will provide novel and important data that will be informative concerning primary prevention through the atherothrombotic pathway. Providing evidence for a reduction in atherosclerosis progression and cognitive decline with nattokinase is likely to shift the current clinical paradigm for the prevention of these chronic age-related processes. In addition, such evidence will serve to create a new field of discovery and opportunity for prevention of cardiovascular disease and dementia.

The Evolutionary Layering of the Mechanisms of Aging

Aging is the accumulation of molecular damage and the consequences of that damage. This molecular damage and its immediate consequences are comparatively simple to describe, but the damage takes place in a fantastically complex system of cells, cellular interactions, tissues, organs, organ interactions, and more. Every problem causes cascading, interacting chains of cause and effect, hard to pick apart via inspection and hard to reason about. Cellular metabolism and tissue structure and function are far from fully mapped, and aging involves sweeping changes throughout the organism and its countless subsystems.

Today's open access paper is an interesting attempt to layer the known hallmarks of aging (which are not all necessarily deeper causes of aging) by how they emerged over time in the evolution of life from unicellular to multicellular and higher organisms. This may well be a useful mental tool when considering the merits of various approaches to the treatment aging, but again, the system as a whole is fundamentally hard to reason about.

The enormous complexity and incomplete understanding of the overlap between aging and cellular biochemistry is why many people are in favor of repair-based interventions as the most effective path forward. There is a better understanding of root causes in aging than there is of how these causes connect in detail to the end consequences of aging. This produces an environment in which the most cost-effective approach is to repair a form of fundamental cell and tissue damage, and see whether or not it produces impressive results in animal studies. Then figure out the details regarding how and why it produces impressive results.

This is how the present focus on senolytic therapies to clear senescent cells emerged. Prior to producing the first demonstration studies of senescent cell removal in mice, not even the researchers who suggested this as a promising line of work thought that this approach to aging would produce rejuvenation in mice to the degree that it does. The exploration of why and how this is so beneficial will take considerably longer than the process of bringing the first useful senolytics into widespread use. Aging is hard to reason about.

The Evolution of the Hallmarks of Aging

The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the "hallmarks of aging," i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging - the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called "layers of aging."

The first layer of aging is the accumulation of unfolded or unstable proteins. As it appears as early as in unicellular organisms, it is universal. In other terms, no species is devoid of at least one mechanism of aging, although in some, its effects are efficiently countered by mechanisms of anti-aging. The first mechanism of anti-aging is disposal of unfolded or unstable proteins by cell division.

The second layer of aging is epigenetic alterations under the form of chromatin remodeling and histone modifications. It has appeared with the evolution of a more sophisticated support for DNA and does not seem to be causally related to the first layer. It concerns all archaea and eukaryotes.

The third layer of aging contains mitochondrial dysfunction, more specifically, ROS damage and the progressive degradation of mitochondrial integrity and biogenesis, damage to mitochondrial DNA and damage to the nuclear architecture, and finally the progressive degradation of proteolytic systems. The appearance of these mechanisms of aging is apparently unrelated to the existence of the previous ones. Yet, interactions are likely: the generation of ROS may increase the number of misshaped proteins, the loss of mitochondrial integrity may increase the generation of ROS. The mechanisms of the third layer result from the appearance of the characteristics of eukaryotic life, the existence of a nucleus, of mitochondria (and chloroplasts), and the appearance of autophagy. All eukaryotes share the mechanisms of this third layer - except those who have possibly lost one of its components.

The fourth layer of aging contains all the mechanisms grouped under the label of 'nutrient sensing': sirtuins and the TOR, AMPK and Insulin - IGF-1 pathways. These mechanisms also appeared independently from mechanisms of the first three layers. However, the level of interactions increases dramatically with this layer, which may be interpreted as a mechanism focused on the management of the available energy sources that happens to control many of the mechanisms of aging of the first three layers (directly with the regulation of autophagy or mitochondrial activity, indirectly through the double role of sirtuins in the regulation of this mechanism and in genomic maintenance), and thereby modulate the rate of aging. These mechanisms characterize opisthokonts, but not all eukaryotes, as their components do not seem to be involved in aging in bikonts, although most of them are present.

These first four layers of aging together constitute the hallmarks of unicellular aging. Unicellular organisms contain some or all of them and most multicellular opisthokonts still contain all of them. In unicellular organisms, the problem of unicellular aging is mainly solved through reproduction, sexual or clonal, which resets the aging clock for at least one of the two cells that result from cell division.

The fifth layer of aging contains DNA methylation and transcriptional alterations. In general, these epigenetic mechanisms, appeared early during the evolution of unicellular organism, have the effect of modulating the expression of genes in a cell, which is necessary to the coordination of individual cells in multicellular life. There is evidence that they are involved as mechanisms of aging in metazoans but it is plausible that they are involved in the aging of a colony in holozoans.

The sixth layer of aging is the decline in the regenerative potential of tissues. It appears with the distinction between stem cells and somatic cells in metazoans. Importantly, this duality of cells is an elegant multicellular solution to the problems of unicellular aging, as long as damaged somatic cells can be renewed, and as the renewal of stem cells can outpace the accumulation of damage as efficiently as prokaryotes get rid of accumulated protein aggregates by sequestrating them into one lineage. When the renewal of cells is insufficient, multicellular organisms age.

The seventh layer of aging contains both inflammation and the accumulation of senescent cells. The mechanisms of aging in this layer are likely to be strongly dependent on the existence of a lower rate of renewal of the cells in a multicellular organism, although they probably originate in some of the specificities of eumetazoans. Inflammation, cell senescence, and the decline in the regenerative potential of tissues together form the engine of aging in most senescent multicellular organisms.

The eighth and last layer of aging contains the accumulation of mutations in nuclear DNA, telomere attrition, and alterations of other forms of intercellular communications as those involved in inflammation. These mechanisms of aging do not depend on the appearance of new entities with bilaterians, but on the considerable complexification of intercellular communication and mutual dependency that appears at this stage, under the constraint of the existence of a complex organization.

The last four layers of aging together constitute the hallmarks of metacellular aging, that is, the aging of the cells of the organism that happens in multicellular life only. Metacellular aging is the problem of aging left unsolved by evolution in many metazoans. It basically consists in the failure to control the effects of unicellular aging, so that they progressively affect the whole multicellular organism, which eventually dies.

In the end, although the multilayer view of aging casts considerable light on the general process of aging, there are three important limitations, that all stem from the essentially 'basic cell biology' approach to aging. The first is that it ignores potentially important non-cellular factors of multicellular aging, like the continuous remodeling, and progressive structural degradation, of the extracellular matrix. The second is that it does not describe how variations of the general mechanism of aging explain the huge variety of the rate of aging among bilaterians. The third is that the importance, and maybe even the implication of some mechanisms of aging may depend on environmental factors.

Dendritic Cells Migrate to the Thymus to Cause Slow Thymic Involution Over a Lifetime

Thymic involution is the process of atrophy observed to take place in the thymus with age. The thymus is a small, but critical organ. Thymocytes produced in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. As active thymic tissue is replaced with fat, the supply of T cells falls to a fraction of youthful levels. This loss of replacement cells is an important contributing factor in the age-related decline of the adaptive immune system. T cell populations come under increasing replicative stress as they strive to maintain a consistent number of circulating cells, while pathological subpopulations of broken and malfunctioning T cells accumulate.

Why does the thymus atrophy? Researchers have studied the signaling involved, and it is reasonable to put much of the blame on rising levels of chronic inflammation with age. That is likely not the whole story, however, as chronic inflammation is a very broad set of mechanisms and interactions, as well as being associated with many other forms of immune dysfunction. We should expect to see discoveries such as that reported in today's open access paper, in which the authors delve into a very specific aspect of immune function that can both correlate with chronic inflammation, and gradually deplete thymic tissue over a lifetime.

Circulating mature dendritic cells homing to the thymus promote thymic epithelial cells involution via the Jagged1/Notch3 axis

The thymus is the central immune organ of the body and critical for T-cell differentiation and development. Many different cell types including thymocytes and thymic stromal cells such as thymic epithelial cells (TECs), resident macrophages, and dendritic cells (DCs) are present in the thymus. As the most crucial stromal cells in the thymus, TECs consist of the cortex and medulla TECs and control the positive and negative selection of T cells. The volumes of the thymic epithelium (cortex and medulla) show a continuous involution from the first year to the end of life. During thymus degeneration, TECs are replaced by fibrocytes and adipocytes. Decreased thymopoiesis leads to a decreased output of naïve T cells with reduced TCR repertoire and diversity. In addition, the number of naïve T cells in peripheral blood decreases gradually.

The increasing evidence demonstrated that peripheral DCs can migrate into the thymus. It was reported that two of the three major subsets of thymic DCs originate extrathymically and continually migrate to the thymus. It has been demonstrated that bone marrow derived antigen-presenting cells (APCs) carrying antigens from the periphery migrate into the thymus and delete autoreactive cells. Futher studies noted that circulating DCs migrated into the thymus and interacted with thymocytes.

In this study, mature DCs (mDCs), generated from the GM-CSF and IL-4 induced bone marrow cells, were intravenously injected into wild-type mice. Three days later, assays showed that the mDCs were indeed able to return to the thymus. Homing DCs have been mainly reported to deplete thymocytes and induce tolerance. However, medullary TECs (mTECs) play a crucial role in inducing immune tolerance. Thus, we evaluated whether the mDCs homing into the thymus led to TECs depletion. We cocultured mDCs with mTEC1 cells and found that the mDCs induced the apoptosis and inhibited the proliferation of mTEC1 cells. These effects were only achieved via direct cell-cell contact between mDCs and mTEC1 cells. Furthermore, we observed that an intrathymic injection of the mDCs resulted in acute thymic atrophy and reduced thymocytes and TECs substantially in vivo. In sum, this demonstrated that circulating mDCs migrated into the thymus and induced the degeneration of the thymus.

Overall, the findings of this study improve our understanding of the mechanisms underlying thymus degeneration. During infection, activated DCs are mature, and migrate into different lymph nodes through afferent lymphatic vessels. DCs, residing in tissues, can reach the periphery and carry antigens to secondary lymphoid organs through blood. A small number of circulating DCs, capturing pathogens, can migrate into thymus. Although the number of thymic homing DCs is relatively small, given numerous mild or severe infections throughout our lifetime, the cumulative effects may contribute to age-related thymus degeneration.

In summary, our results provided evidence that circulating mDCs return to the thymus and interact directly with TECs to activate Notch signaling through the Jagged1/Notch3 axis. Long-term Notch signaling activation of TECs results in their apoptosis and growth inhibition, thus leading to the degeneration of the thymus. These results also provide insights into the mechanisms underlying age-related thymic atrophy or infection, organ transplant rejection, and other diseases related acute thymic atrophy and help to develop novel strategies in clinical thymus and T-cell reconstruction.

How Much of Cardiovascular Disease is Self-Inflicted?

Atherosclerosis, the buildup of fatty plaques in blood vessel walls, is an inevitable outcome of aging, driven by chronic inflammation, oxidative stress, and other processes that cannot be evaded without the development of new approaches to medical biotechnology. The pace at which this becomes a fatal condition is heavily driven by lifestyle choices, however. All of the usual activities and decisions that physicians tell us to avoid will, over time, lead to a faster progression of atherosclerosis, and a greater risk of mortality due to the rupture or blockage of blood vessels. It is quite possible that many people will be saved from their own neglect by new medical therapies that emerge in the years ahead. Equally, why roll the dice on the speed of medical progress, when you can postpone that need?

As much as 90% of the risk of a heart attack, stroke, or peripheral arterial disease (PAD) can be explained by smoking, poor eating habits, lack of physical activity, abdominal obesity, high blood pressure, raised blood lipid levels, diabetes, psychosocial factors, or alcohol. These guidelines focus on atherosclerotic cardiovascular disease (CVD), which affects the arteries. As the inside of the arteries become clogged up by fatty deposits, they can no longer supply enough blood to the body. This process is the main cause of heart attacks, strokes, PAD and sudden death where arteries become completely blocked. The most important way to prevent these conditions is to adopt a healthy lifestyle throughout life, especially not smoking, and to treat risk factors.

Targets for blood lipids, blood pressure, and glycaemic control in diabetes remain as recommended in recent guidelines on dyslipidaemias, hypertension, or diabetes. The current guidelines introduce a stepwise approach to intensifying preventive treatments, while always taking into consideration potential benefit, other conditions, psychosocial factors and patient preferences. In healthy people, for example, the stepwise approach starts with recommendations for everyone: smoking cessation, adopting a healthy lifestyle, and maintaining a systolic blood pressure below 160 mmHg.

Stopping smoking is potentially the most effective of all preventive measures, with substantial reductions in heart attacks or death. The CVD risk in smokers under 50 years of age is five-fold higher than in non-smokers. Quitting must be encouraged in all smokers, and passive smoking should be avoided where possible. Regarding nutrition, a healthy diet is recommended for all individuals to prevent CVD. This should emphasise plant-based foods including whole grains, fruits, vegetables, pulses, and nuts. New recommendations include the adoption of a Mediterranean or similar diet.

In terms of body weight, it is recommended that overweight and obese people lose weight to lower blood pressure, blood lipids, and the risk of diabetes, and thereby reduce the likelihood of CVD. For the first time, the guidelines state that bariatric surgery should be considered for obese individuals at high risk of CVD when a healthy diet and exercise do not result in maintained weight loss.

Altos Labs Formed to Work on the Treatment of Aging

It remains to be seen as to whether Altos Labs is the new, large venture that patient advocates for the treatment of aging have been alluding to cryptically in recent months. It is apparently backed by a number of the high net worth individuals in the Left Coast business and philanthropy communities who are known to have a growing interest in the application of biotechnology to aging. Sadly, recent history suggests we should not expect much from such initiatives. Neither the Ellison Medical Foundation nor Calico Labs have done more than take on more of the same fundamental research into the progression of aging that is carried out at the NIA, at great expense, but no great gain. This is work that will not lead to rejuvenation therapies, and in many cases cannot even in principle achieve much in the matter of treating aging. The path to rejuvenation is to repair the known causes of aging and see what happens as a result. Unfortunately, most of the field spends most of its time trying to decipher how exactly aging proceeds in its complex later stages of cell and tissue dysfunction, without attempting to address those causes. Perhaps Altos Labs will be a different beast, given the apparent focus on cellular reprogramming. We can certainly hope so.

Last October, a large group of scientists made their way to Yuri Milner's super-mansion in the Los Altos Hills above Palo Alto. They were tested for covid-19 and wore masks as they assembled in theater on the property for a two-day scientific conference. Others joined by teleconference. The topic: how biotechnology might be used to make people younger. Milner previously started the glitzy black-tie Breakthrough Prizes, 3 million awards given each year to outstanding physicists, biologists, and mathematicians. But Milner's enthusiasm for science was taking a provocative and specific new direction. As the scientific sessions progressed, experts took the stage to describe radical attempts at "rejuvenating" animals.

That meeting has now led to the formation of an ambitious new anti-aging company called Altos Labs, according to people familiar with the plans. Altos hasn't made an official announcement yet, but it was incorporated in Delaware this year and a securities disclosure filed in California in June indicates the company has raised at least 270 million. Altos is pursuing biological reprogramming technology, a way to rejuvenate cells in the lab that some scientists think could be extended to revitalize entire animal bodies, ultimately prolonging human life. The new company, incorporated in the US and in the UK earlier this year, will establish several institutes in places including the Bay Area, San Diego, Cambridge, UK and Japan, and is recruiting a large cadre of university scientists with lavish salaries and the promise that they can pursue unfettered blue-sky research on how cells age and how to reverse that process.

Altos is certain to draw comparisons to Calico Labs, a longevity company announced in 2013 by Google co-founder, Larry Page. Calico also hired elite scientific figures and gave them generous budgets, although it's been questioned whether the Google spinout has made much progress. Calico has also started a lab whose focus is reprogramming; it published its first preprint on the topic this year.

More Blood Pressure Control is Better than Less Blood Pressure Control

The epidemiological evidence of recent years shows that a greater control of blood pressure is beneficial, reducing mortality and incidence of age-related conditions. Hypertension, raised blood pressure, is characteristic of age and very damaging to fragile tissues throughout the body. That damage adds up over time, and is a major contribution to age-related degeneration. A sizable component of age-related hypertension is lifestyle related, rather than an inexorable consequence of the mechanisms of aging, and thus avoidable. Further, a range of comparatively safe drugs can force a lowering of blood pressure, overriding dysfunction in blood pressure regulation. Even without addressing underlying causes related to the mechanisms of aging, this can produce a meaningful reduction in mortality and cardiovascular disease.

Aggressive blood pressure treatment in older hypertensive patients lowers the incidence of cardiovascular events compared to standard therapy, without increasing adverse outcomes. More than one billion people have hypertension worldwide. The overall prevalence in adults is around 30-45%, rising to more than 60% of people over 60 years of age. As populations age, adopt more sedentary lifestyles, and increase their body weight, the prevalence of hypertension worldwide will continue to rise. Elevated blood pressure was the leading global contributor to premature death in 2015, accounting for almost 10 million deaths.

The STEP study was conducted to provide new evidence on the benefits of blood pressure lowering in older patients with hypertension. Specifically, it examined whether intensive treatment targeting a systolic blood pressure (SBP) below 130 mmHg could reduce the risk of cardiovascular disease compared with a SBP target below 150 mmHg. The study enrolled 8,511 older essential hypertensive patients from 42 clinical sites in China. All participants were aged 60-80 years, with a SBP of 140-190 mmHg during three screening visits or taking antihypertensive medication. Patients with prior stroke were excluded.

Participants were randomly assigned to 1) intensive treatment (SBP target below 130 mmHg but no lower than 110 mmHg); or 2) standard treatment (SBP target 130-150 mmHg). uring a median 3.34-year follow-up period, the average decrease in SBP from baseline was 19.4 mmHg in the intensive treatment group and 10.1 mmHg in the standard treatment group. Average SBP reached 126.7 mmHg and 135.9 mmHg in the intensive and standard groups, respectively, with an average between-group difference of 9.2 mmHg.

The primary outcome was a composite of stroke, acute coronary syndrome, acute decompensated heart failure, coronary revascularisation, atrial fibrillation, or death from cardiovascular causes. A total of 196 primary outcome events were documented in the standard treatment group (4.6%) compared to 147 events in the intensive treatment group (3.5%), with a relative risk reduction of 26%.

Correlations Between p53 Sequence Differences and Species Lifespan

All other things being equal, more cells in the body undertaking more activity means a larger risk in any given period of time of one of those cells undergoing a cancerous mutation. Given this, larger and longer-lived species have necessarily evolved superior mechanisms of cancer suppression in order to avoid early death by cancer. The protein p53 is a cancer suppressor, produced from the gene TP53. Large mammals such as elephants maintain a low risk of cancer, despite having many more cells than smaller mammals, in part via having many copies of TP53 in the genome. It isn't just copy number, however. The sequence of p53 varies in small ways from species to species, and researchers here show that some of those differences appear to correlate with species longevity.

p53 is a critical sensor of cellular stress and thus, the dictator of cell fates. Depending on the types of stress, which include DNA damage, oncogene activation, nutrient deprivation, reactive oxygen species accumulation, and telomere shortening, p53 either (1) transiently stops cell proliferation, initiates the DNA repair machinery, and induces cell death when the damage cannot be repaired, or (2) pushes cells to replicative senescence, which is a permanent proliferation arrest.

Long-lived, cancer-free African elephants have 20 copies of the TP53 gene, including 19 retrogenes (38 alleles), which are partially active, whereas humans possess only one copy of TP53 and have an estimated cancer mortality rate of 11-25%. The mechanism through which p53 contributes to the resolution of Peto's paradox of cancer incidence remains vague. Thus, in this work, we took advantage of the available datasets and inspected the p53 amino acid sequence of phylogenetically related organisms that show variations in their lifespans.

We discovered new correlations between specific amino acid deviations in p53 and the lifespans across different animal species. We found that species with extended lifespans have certain characteristic amino acid substitutions in the p53 DNA-binding domain that alter its function. In addition, the loop 2 region of the human p53 DNA-binding domain was identified as the longest region that was associated with longevity. A 3D model revealed variations in the loop 2 structure in long-lived species when compared with human p53. We speculate that in long-lived species, L2 affects the p53 binding to DNA and/or other transcription factors and, consequently, affects the replicative senescence program.

ILC2 Immune Cells Become Altered with Age in Ways that Impair Thermoregulation

Older mammals are prone to impaired thermoregulation, such as the inability to generate sufficient warmth in response to cold temperature. Researchers here find that changes in the population of ICL2 immune cells in fat tissue are important in this dysfunction. Transplanting young immune cells into old mice appears to help, but that demonstration is just the starting point. Researchers will now have to work their way down the long road to a sufficient understanding of the underlying mechanisms to enable a cost-effective forms of intervention. How does this dysfunction connect to the underlying cell and tissue damage of aging? That question will likely remain open for some years.

Human evolution has provided us a level of protection from the existential threat of cold temperature with the capacity to produce heat from fat stored in the body. However, with age, people become more susceptible to cold as well as inflammation and metabolic problems which can lead to a host of chronic diseases. In a new study, researchers find that the fat tissue of older mice loses the immune cell group 2 innate lymphoid cells (ILC2) which restore body heat in presence of cold temperatures. But in a cautionary tale for those seeking easy treatments for diseases of aging, they also found that stimulating production of new ILC2 cells in aging mice actually makes them more prone to cold-induced death.

Researchers were curious about why fat tissue harbors immune system cells, which are usually concentrated in areas often exposed to pathogens like nasal passages, lungs, and skin. When they sequenced genes from cells of old and young mice they found that older animals lacked ILC2 cells, a deficit which limited their ability to burn fat and raise their body temperature in cold conditions. When scientists introduced a growth factor that boosts the production of ILC2 in aging mice, the immune system cells were restored but the mice were surprisingly even less tolerant of cold temperatures.

"The simple assumption is that if we restore something that is lost, then we are also going to restore life back to normal. But that is not what happened. Instead of expanding healthy cells of youth, the growth factor ended up multiplying the bad ILC2 cells that remained in fat of old mice." But when researchers took ILC2 cells from younger mice and transplanted them into older mice, they found that the older animals' ability to tolerate cold was restored.

Questioning the Reproducibility of Fly Life Span Studies

In the course of examining gender differences on fly longevity, researchers here find sizable variations in life span between repeated studies. This variation is thought to derive from differences in maintaining a fly population, such as the dietary composition and season of the year. They suggest that this calls into question the detailed data obtained from much of the work involving aging and age-slowing interventions in flies. Reproducibility is critical to establishing whether or not observed effects are real. Flies may thus be a poor choice of model organism for any initial investigation of means to slow or reverse aging.

While our original goal was to understand how genetic variation played a role in costs of reproduction, we discovered strong cohort effects from one study to the next, especially across years. While we did not interrogate environmental and husbandry effects during the course of this experiment, we can surmise that these two factors were the major drivers of the differences we saw between the two replicate experiments, as genetic backgrounds were mostly comprised of iso-female lines.

The largest discrepancies between two years were seen with regards to maximum lifespans. While median lifespans were not changed to a large degree between years/seasons, maximum lifespans were significantly longer in summer 2019 in both sexes. We have several hypotheses, all related to fly husbandry, that could potentially explain this discrepancy. Our most likely, and anecdotally supported, hypothesis is that flies living in the summer are able to maintain better water homeostasis than those in the winter. Even though the incubators were set to approximately 60% humidity, we know that these often fluctuate. A second hypothesis for our observations is that the two experiments were done on slightly different media. As fly diet can have a huge impact on health and longevity, this could be contributing to our observed differences.

This lack of reproducibility in significant results between our two cohorts suggests that for certain questions the use of iso-female strains for determining genes that affect different phenotypes will require exquisite attention to husbandry details. The Drosophila Genetics Reference Panel (DGRP) has been used over the past decade to measure dozens of different biological phenotypes with conclusions about the genes playing a causal role in the phenotypes in question. However, if small environmental perturbations can make such differences in something a fundamental as sex differences in longevity, it is possible that many phenotypes may be more sensitive to subtle environmental variation than is generally supposed. As the fruit fly is used as the primary model organism to test novel compounds for their lifespan-extending effect, our results suggest that reproducibility between and even within laboratories might prove difficult.

Quantifying the Effects of a Five Day Fast for Comparison with Fasting Mimicking and Calorie Restriction

One of the more interesting developments of recent years in work on the beneficial effects of calorie restriction in humans is the establishment of an optimal boundary of reduced calorie intake. Can one obtain near all the benefits of fasting by eating a little, and how much is "a little" in this context? That question led to the fasting mimicking diet, supported by evidence for "a little" to be something like 750 calories per day for an averagely sized human, when considering a five day fast or low-calorie diet. As researchers note here, improvements in many metabolic parameters are not very different when considering fasting versus a fasting mimicking low calorie intake on this time frame. A range of other topics are also under exploration, such as how long the benefits to metabolism last following a fast, how long one has to fast to obtain those lasting benefits, how frequently to fast, and so forth. But it is always good to see an accumulation of more data and more robust data on these topics.

Fasting is known to have many health benefits such as prolonging lifespan and suppression of tumorigenesis. In the present study, we systematically evaluated the effects of water-only fasting on metabolic-syndrome and age-related risk markers in 45 normal-weight individuals. As shown, a 4.59 kg reduction in body weight, 9.85 cm reduction in waist circumference, and 1.64 kg/m2 reduction in body mass index (BMI) were observed during a 5-day water-only fast. After refeeding for 1 month (day 38), body weight, waist circumference, and BMI were still lower than the baseline level.

Blood pressure (BP) significantly declined during water-only fasting with diastolic BP declining more than systolic BP and gradually both increased to the baseline level by 98 days. Considering many fasting studies showed diastolic BP reduction did not exceed systolic BP reduction, future studies are needed on water-only fasting and BP reduction. Insulin dropped approximately 2.8-fold lower than the baseline level during water-only fasting. Insulin-like growth factor 1 (IGF-1) decreased by a total of 26% during water-only fasting and decreased more in females than males.

The number of pan T cells, CD4+T cells, CD8+T cells, and B cells decreased during water-only fasting. In contrast, the frequency of Treg cells significantly increased during fasting and still exceeded the baseline level 3 months after refeeding. This is an important benefit, since Treg cells have anti-inflammation effects. With regard to thyroid hormones, T4 increased rapidly during fasting, whereas T3 and TSH decreased. The decreased level of T3 during water-only fasting is of particularly importance since a low T3 level, without impairing thyroid function, is strongly associated with longevity.

The present study suggested that water-only fasting for many parameters was similar to calorie restriction and a fasting-mimic diet.The results of the present study are very promising as 5-day water-only fasting has many critical beneficial effects without toxicity.

Protection versus Harm: Cellular Senescence in the Context of Cancer

A little cellular senescence is a good thing. When a cell enters the state of senescence in response to potentially cancerous mutational damage it shuts down replication and secretes signals that attract the immune system. Immune cells destroy any such senescent, damaged, potentially dangerous cells that fail to destroy themselves. When senescent cells accumulate with age, however, as the immune system falters in its task of clearance, the inflammatory secretions of these errant cells - the senescence-associated secretory phenotype (SASP) - make the environment much more favorable for the creation and growth of cancer.

Cellular senescence provides a significant benefit to the host by inducing irreversible cell cycle arrest and eliciting potent immune-mediated incipient tumor cell clearance, which is characterized by reduced incidence of cancer and halted tumor development. Senescence provides an alternative strategy to overcome the limitations of traditional cancer treatment because low dose of drugs can achieve the purpose of inducing senescence. However, senescent cells and SASP components can directly or indirectly promote tumor cells growth, invasion, and metastasis, and tumor vascularization. The senescence phenotype is complicated, and the production rate and clearance rate of senescent cells may be the influencing factors of the effects of senescence on tumor progression. One of the possibilities is that senescent cells are only beneficial when they are transient, and the accumulation of senescent cells and SASP cause increased susceptibility to tumorigenesis.

The in-depth understanding and utilization of senescence in cancer therapy has gained increasing attention and has become an important research field. A growing number of studies have convincingly demonstrated a paradoxical role for spontaneous senescence and therapy-induced senescence (TIS), that senescence may involve both cancer prevention and cancer aggressiveness. Previous findings have indicated that TIS is a positive outcome of therapy, since senescence is a state of growth arrest reflecting the loss of reproductive potential. In order to overcome the negative effects of TIS in cancer treatment, the concept of combining senescence-inducing therapies and removal of senescent cells, both normal and tumor derived, via senolytic therapies, or manipulating the paracrine effects of SASP is proposed. However, before clinical application, we must balance the validity and potential risks, and determine the overall advantages of this treatment concept.

Mitochondrial-Derived Peptides as Targets for Cardiovascular Disease Therapies

This review takes a look at a number of peptides related to mitochondrial function, and which are thought to potentially provide therapeutic benefit. Some are interesting in the context of aging. As is the case for most peptides with enough scientific literature to justify a review paper, availability and use is somewhat ahead of the science. Peptide manufacture is easy enough and cheap enough that most studied peptides can be purchased from established manufacturers. That certainly doesn't mean that they are in fact useful at the end of the day! This marketplace is very much like the supplement marketplace in that respect: there is a great deal more marketing than there is truth and robust evidence of benefits. That a mechanism exists, and connects to aspects of aging, such as mitochondrial dysfunction, is no guarantee that manipulating it will have a large enough effect to matter.

Mitochondria-derived peptides (MPDs) are a class of recently identified peptides, which are found within other known mitochondrial genes and encoded by small open reading frames (ORFs). The first MDP, Humanin (HN), was discovered in 2001 in patients with Alzheimer's disease and described as a neuroprotective peptide with a high therapeutic potential for neurodegenerative diseases. After HN, two other types of MDPs were discovered: mitochondrial ORF of the 12S rDNA type-c (MOTS-c) and small Humanin-like peptide, 1 to 6 (SHLP1-6).

MDPs are widely presented in different tissues, such as the kidney, skeletal muscle, colon, vascular wall, and heart. MDPs are released into the body via paracrine and endocrine pathways and have diverse functions as cytoprotective agents, such as maintaining cell viability and mitochondrial function under stress, are involved in cellular metabolism and cell survival and act in response to inflammation and oxidative stress. Recently, the role of MDPs was highlighted for many senescence and ageing-associated diseases, chronic inflammation diseases, cancer and neurodegenerative diseases, and retinal and fertility diseases.

In this review, we focus on the role of on MDPs as crucial peptides, modulating and regulating mitochondrial function and involved in pathological changes in cardiovascular disease via different molecular mechanisms. We also discuss the application of MDPs, modified MDPs and synthetic MDPs as uprising pharmaceutical tools for the treatment of cardiovascular diseases and other conditions. Further understanding the role of MDPs in various signalling pathways related to CVD would improve its medical significance and therapeutic potential.

Impetus Grants for Longevity Research

I wholeheartedly approve of the approach taken by the organizers of the Impetus Grants project. If one has the funds to influence the course of science, then this is a smart way to go about it. Pick a field and a goal that interests you, and place funds in the hands of researchers with as little red tape and infrastructure as possible. Arrange for publication of data in advance, to ensure that all that is learned will be propagated to the rest of the field. The only real challenge in setting up such a venture is to learn enough about the field in order to be able to pick a good supporting team of scientific advisors and reviewers, people who are willing to be something other than conservative. The overhead to direct as much as tens of millions into constructive fundamental research can be quite minimal in this model.

Impetus Grants provides funding for scientists to start working on what they consider the most important problems in aging biology, without delay. Such work should not be held up by red tape: we offer grants of up to 500,000, with decisions made within 3 weeks. Our review process asks "what's the potential for impact" rather than "could this go wrong".

Our goal is to have a broad impact on the field, by supporting projects that challenge assumptions, develop new tools and methodologies, discover new ways to reverse aging processes, and/or synthesize isolated manifestations of aging into a systemic perspective. To ensure that we learn from every project, we're organizing a special issue of GeroScience to provide an opportunity to publish both positive and negative results from funded studies. We would rather fund the work you are most excited about doing, even if it might fail, than work that is certain to produce results but with limited impact on the field. But we realize that proposed projects will be done in the context of existing publication incentives.

We provide anywhere from 10,000 to 500,000. We do consider the amount requested during review; all else equal, projects that require less funding will be favored. We will pay a maximum of 10% institutional overhead, in line with the Gates Foundation precedent. Your application will be reviewed by at least two reviewers with more than a decade of experience in aging research, and at least one reviewer who is a topic expert for your proposal. All of our reviewers are under NDA to preserve confidentiality of your proposal. All projects will be evaluated on the clarity and quality of their experimental plans, and on the scope and immediacy of their potential impact on the longevity field. We ask 'could this work' rather than 'could this fail', and are not looking for complete consensus among reviewers; if at least one reviewer is strongly supportive of the project, we will tend to fund it.

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