Fight Aging! Newsletter, October 4th 2021

A key current limitation in the longevity field is that deep biological studies on individual interventions have primarily been investigated independently and in an ad hoc fashion, leading to a lack of comprehensive data on any one intervention. One project examines brain aging but doesn't measure lifespan, while another measures metabolism but doesn't track epigenetics, and yet another looks just at lifespan itself. This fractured approach makes it difficult to compare or combine aging interventions within a common framework.

To resolve this problem, the Rejuvenome will conduct a large-scale experiment in genetically diverse mice to measure system-wide multi-omics spanning a panel of rejuvenation interventions. By measuring multiple hallmarks of aging across the lifespan of mice, the project will provide a high-resolution description of the interconnection or independence of different aspects of the aging process and of how interventions alter these pathways. The resulting intervention-effect matrix will support the field in its advance towards better interventions.

Ultimately, the Rejuvenome will test combinations of interventions designed to target multiple aspects of aging simultaneously. There is good reason to believe such combinations will produce synergistic effects. Multiple gene knockouts in C. elegans have been shown to increase lifespan by 10x, and a combination of three compounds extended lifespan in flies beyond the effects of any of the individual components - a similar multifaceted approach could produce the longest living mice and suggest potential future multi-factorial therapies for humans.

The Astera Institute was created to bring humanity the greatest imaginable good in the most efficient possible way. When your ambitions are boundless, but your resources are finite, leverage is your friend. In the words of Konrad Zuse, "I was too lazy to calculate, so I invented the computer." Inspired by such extreme examples of "work smarter," Astera seeks to activate the areas of exponential latent potential within science and technology. We want to create benevolent super-intelligence, live to 200, fix science, and do engineering worthy of Asimov. Astera Institute was established by Jed McCaleb. It is a 501c3 non-profit dedicated to developing high leverage technologies that can lead to massive returns for humanity. Astera's unusually high impact derives from housing moonshots and novel scientific research that have no other natural home in today's research and development landscape. Astera focuses on longevity, AGI, metascience, and frontier engineering.

If we look at the maintenance approach, the damage repair approach, that, of course, I founded more than 20 years ago now, that has become very much the focus or one of the major focuses of the anti-aging research field. We can see that potentially, there is a bit of an issue, because there are lots of different types of damage that we have to go after.

Of course, the whole reason why geriatric medicine was originally seen to be a non-starter that would never really have all that much effect on the healthspan of the human race was because of that precise problem that there are so many things you have to fix. The maintenance approach kind of sidesteps that; it makes the divide-and-conquer problem more manageable in ways that I've talked about many times and I won't reiterate now.

But still, it's a divide-and-conquer problem. And that means that we have to make quite sure that the most difficult parts of that divide and conquer approach are not left behind and neglected. Of course, SENS Research Foundation was set up more than a decade ago, with exactly that in mind; we set it up as an independent charity, an independent nonprofit funded almost entirely by philanthropy.

We did that precisely in order to avoid the constraints that forced both industry and mainstream academia into short-termism into focusing on low-hanging fruit and neglecting the harder but equally important problems that otherwise they might work on. Of course, the past decade of work that we and others have done, has had great successes, and certainly some of those successes constitute progress in the most difficult areas of damage repair.

For example, in the area of mitochondrial mutations, in the area of extracellular matrix stiffening, these are areas which were completely stalled when we started, and they're not stalled anymore. But they're still nowhere near as far along as getting into clinical trials, for example. So we've got to make absolutely sure that that does not persist, that these things are continuing to be pushed forward.

That's where emerging challenge number one is: it is extraordinarily hard to get most people to not focus on the low-hanging fruit. In industry, of course, we know that people who want to make money, they want to make it soon, and therefore they are going to put pressure on to cause that to happen. Some of you who have long memories may recall a company called Elixir Pharmaceuticals, which were founded by two absolute demigods of gerontology, Cynthia Kenyon and Leonard Guarente. The reason why those of you with short memories will probably not remember Elixir is because it ended up being a complete waste of time. That was why: they took the wrong money, they got pressured into doing stuff that wasn't useful, and nobody remembers them at all.

It's, of course, exactly the same in academia, that short-termism arises from the need to publish or perish. And same result. The worst of it is that it's quite easy in biology in general, and certainly in our field, to identify areas where you can make quick progress and make a big splash and get a terribly interesting paper on the front page of Science Magazine. Unfortunately, it doesn't go anywhere, because there is no actual way to take it forward to something that would have clinical relevance in the long run.

And the final problem, a final aspect of this problem, is that most of the real visionaries who have money are actually capitalists: they are people who made their money in the private sector, and they believe in that kind of way of doing things. Many of them simply do not believe in philanthropy, or in charity in general.

Now, some of those people have been visionary enough to recognize that they have to bite that bullet. Of course, the person who gets the greatest credit for that in our world is Peter Thieltps://en.wikipedia.org/wiki/Peter_Thiel">Peter Thiel, who started funding Methuselah Foundation back in 2006. But the fact is now that these people have the opportunity to invest rather than to donate, they are very, very tempted to do exactly that. So we absolutely need to be vigilant in making sure that the most difficult components of the damage repair portfolio are not neglected.

The chronic kidney disease (CKD) phenotype is very similar to premature ageing. Frailty, osteoporosis, muscle wasting, and cardiovascular disease occur at a younger age in CKD patients. Many factors such as oxidative stress, accumulation of uremic toxins, and inflammation are supposed to contribute to accelerated ageing. The immune system undergoes a similar premature ageing. Patients with end-stage renal disease (ESRD) frequently exhibit T cell lymphopenia and concomitantly have both a marked susceptibility for infections and a decreased response to vaccines suggesting a T cell immune defect. Finally, ESRD patients exhibit a low-grade inflammation status. This association is typical of the "inflammaging" state observed in elderly.

The term immune senescence clusters all the changes that occur in the immune system during ageing. Although this process mainly affects T lymphocytes, all aspects of innate and adaptive immunity are concerned. The ageing of the immune system is a more general concept including two different processes. The first one is what is specifically referred to by immune senescence, which is mainly linked to age-dependent thymic involution leading to reduced immune repertoire diversity and compounded oligo-clonal increase in memory immune cells. Sensitivity to infections, reduced vaccine immunity, and defect in tumour clearance observed in elderly are thought to be at least in part linked to these immune alterations. The second characteristics of aged immunity is inflammaging. Old age is associated with low-grade systemic inflammation. Chronic innate immune activation, pro-inflammatory cytokine profile secretion, and age-induced accumulation of self-reactive T cells contribute to age-related inflammation. Inflammaging is supposed to explain some degenerative disease associated with ageing.

Premature thymic involution is a key component of ESRD-associated immune senescence. It is reported that thymic output decreased with progression of CKD. Thymic output is comparable between 40-year-old uremic patients and 80 year-old non-uremic patients. Our group recently reported that, in ESRD patients, low thymic output was predictive of severe infections. The decrease in recent thymic emigrant cells could be the result of a reduction in the thymic output of naïve T cells and/or of a reduction in homeostatic proliferation. Premature loss of thymic function is likely to explain the decrease in naïve T cells in young patients with ESRD.

However, there are few data documenting potential causes for premature thymic involution during chronic kidney disease. Chronic inflammation is likely to markedly contribute to immune ageing. Of note, a recent study shows that C-reactive protein levels inversely correlates with naïve T cells in haemodialysis patients suggesting either that inflammation and immune senescence evolve in parallel or that one is driving the other one. Activation of innate immunity, characterised by monocyte activation and overproduction of inflammatory cytokines such as IL-6, is a key feature of the CKD immune system. Treating reversible source of inflammation is obviously a goal in CKD patients and such strategy may reduce premature ageing.

Immune senescence has deleterious consequences. Susceptibility to infection, premature cardiovascular disease, and increased cancer incidence are some of the most frequent and serious. A number of measures, from the simplest to the more complex, may be susceptible to reverse immune senescence, especially premature thymic involution.

Firstly, the impact of physical activity in maintaining thymic activity must not be neglected. It is one of the rare therapeutic strategies with consistent results in both animal and human studies. In an immunological ageing mouse model, 4 weeks of free-wheel running increased naïve T lymphocytes and reduced effector ratio of cytotoxic T lymphocytes. Concordant data also exist in humans. Physical activity is often reduced in CKD patients. Sedentary life, socio-economics conditions, comorbidities, and uremia-related asthenia contribute to the reduced physical activity. Although a large number of studies reported the beneficial effects of exercise in CKD patients, no data are available concerning the potential consequences on immune status. However, other benefits of physical exercise in ESRD patients have been largely reported and physical rehabilitation programs should be encouraged in these patients.

Secondly, many hormonal pathways play a role in thymic physiology. However, most of them are impaired during chronic renal failure. The IGF-1-GH pathway interferes with many aspects of thymus biology. The IGF-1-GH axis is profoundly altered in dialysis patients. ESRF patients have increased GH secretion, but normal IGF-1 concentrations, indicating GH resistance. This suggests that GH may be a therapeutic hope to reverse thymopoiesis defect in ESRD patients.

The effects of sex hormones on thymus are well-known. A number of studies demonstrated that sex steroid ablation delay or reverse thymus involution in both animals and humans. Surgical castration is obviously not a therapeutic option in humans, but LHRH analogues use is also associated with thymic rejuvenation. Nevertheless, some studies also suggest that castration-induced thymic rejuvenation is only transient and potentially hazardous. Despite some former results, the use of chemical castration to enhance thymic rejuvenation is consequently not a safe option.

Some cytokines may also promote thymic function. IL-7 is produced by both thymic stromal cells and bone marrow. IL-7 mediates lymphopoiesis of both T cells and B cells, and in the thymus, promotes proliferation, differentiation, and survival of thymocytes. Administration of IL-7 in mice expand both naïve and memory CD4 and CD8 peripheral T cells. IL-22 interacts with IL-2R on the surface of thymic epithelial cells and allows both survival and proliferation of thymocytes. IL-22 administration to mice having received total body irradiation increases both thymocytes and thymic epithelial cell recovery. Limitations in the therapeutic use of IL-22 are based on its dual effects, which strictly depend on the context. The pro-regenerative effects of IL-22 could be counterbalanced by its inflammatory and tumorigenic properties.

KGF belongs to the fibroblast growth factor family. This cytokine is involved in epithelial cell proliferation and differentiation in many tissues, including the thymus. KGF administration to mice enhance thymopoiesis and accelerate thymic recovery after irradiation.. In non-human primates, KGF enhances immune reconstitution after autologous hematopoietic progenitor cell transplantation. More recently, conflicting results made the benefits of KGF less clear. In HIV-infected patients, KGF was not effective in either improving thymic function or rising circulating CD4+ T cells.

Forced expression of FOXN1 in involuted thymus results in thymic regeneration with increased thymopoiesis and naïve T cell output. The structure of the regenerated thymus was very close to young thymus in terms of architecture and gene expression. These results suggests that up-regulation of FOXN1 is sufficient to reverse age-related thymic involution. Further, recombinant FOXN1 protein fused with cell-penetrating peptides increased the number of thymic epithelial cells and enhanced thymopoiesis after hematopoietic stem cell transplantation in mice. All together, these studies suggest that the FOXN1 axis research is a valuable strategy to reverse thymic involution. To date, there are no evaluation of FOXN1 expression during CKD.

The gut microbiota interferes with the immune system lifelong and its dysregulation results in inflammation. Whether microbiota interferes with immune senescence is challenging because the relative part of microbiota and health status are difficult to isolate. Moreover, even when dysbiosis may favour inflammation, inflammation may also promote dysbiosis asking the question of which came first. Dysbiosis is a hallmark of chronic kidney disease. Accumulation of uremic toxins in CKD causes substantial modifications in gut physiology. Evidence suggests that septic inflammation observed in ESRD is at least in part related to a shift toward more inflammatory microbiota.

In conclusion, premature thymic involution and chronic inflammation greatly contribute to increased morbidity and mortality in CKD patients. Mechanisms are likely to be multiple and interlinked. Even when the quest to fountain of youth is a pipe dream, there are many scientific opportunities to prevent or to, at least in part, reverse CKD-related immune senescence. Further studies should precisely define most important pathways driving premature immune ageing in CKD patients and best therapeutic options to control them.

Notably, the societal triumph of longevity is plagued with debilitating morbidity, accentuated towards the end of life. The average life expectancy - a benchmark of population health - has risen from 47 to 73 years of age in these seven decades, a 26-year expansion. This remarkable trajectory in human longevity has generated a redistribution in demographic structure underpinned by a disproportionate surge in those over 70 years of age. Notably, the societal triumph of longevity is plagued with debilitating morbidity, accentuated towards the end of life.

Lifelong (also referred as "chronic" or "non-communicable") diseases are the leading cause of mortality and disability worldwide. Collectively, chronic diseases are responsible for 40 million or 71% out of 56 million annual deaths globally, and 79% of all years lived with disability. Four common conditions, namely cardiovascular diseases, cancer, diabetes, and chronic respiratory diseases, account for 80% of chronic disease related deaths. The imposed socioeconomic burden is estimated to represent a 47 trillion loss over the last two decades. Fifty-eight percent of chronic disease-related mortality occurs in persons over 70 years of age. This growing age segment thus warrants special attention.

Age-associated outcomes are profoundly aggravated by frailty. Indeed, there is a recognized gap between lifespan, i.e., the total life lived, and healthspan, i.e., the period free from disease. Using health-adjusted life expectancy, that considers life expectancy, years lived with disability, and premature death from disease, the healthspan-lifespan gap is estimated at around 9 years. This gap appears refractory to current practice paradigms. In fact, one-fifth of an individual's life will be lived with morbidity. Extending lifespan alone without delaying disease onset and/or reducing disease severity would actually aggravate the healthspan-lifespan gap.

The insidious accumulation of chronic disease and frailty must engender disruptive innovation. Targeting the root cause at latent stages offers the prospect of implementing proactive, prophylactic actions. Growing regenerative options offer opportunities to boost innate healing, and address aging-associated decline. Diverse aging populations are thus at the cusp of a promising horizon.

Atherosclerosis, or the buildup of fatty deposits in blood vessels that supply blood to the heart, is a major cause of heart attacks. A widely used approach to screen people who are at risk for heart disease but who do not yet have symptoms is cardiac computed tomography, commonly known as a cardiac CT scan, for coronary artery calcification (CAC) scoring. The scan creates cross-sectional images of the vessels that supply blood to the heart muscle to measure the presence and density of calcium-containing plaque in the coronary arteries. However, CAC scoring can miss a percentage of people who are at risk for heart attack even though they have a zero CAC score. "Measuring the amount of calcification is important, yet it does not give information about non-calcified atherosclerosis, which also increases heart attack risk. Non-calcified atherosclerosis is believed to be more prone to cause heart attacks compared with calcified atherosclerosis."

Researchers randomly recruited participants aged 50-64 years old from the Swedish census register from 2013 to 2018 as part of the Swedish CArdioPulmonary BioImage Study (SCAPIS). They report on data from 25,182 participants with no history of a prior heart attack or cardiac intervention who underwent both CAC scans and coronary computed tomography angiography (CCTA) scans. CCTA is a radiologic technique that gives a very detailed image of the inside of the arteries that supply the heart with blood. The researchers wanted to determine the prevalence of atherosclerosis in the general population without established heart disease, and how closely the CCTA findings correlated to CAC scores.

CCTA detected some degree of atherosclerosis in more than 42% of the study participants. CCTA found that in 5.2% of those with atherosclerosis, the build-up obstructed blood flow through at least one coronary artery (out of three) by 50% or more. In nearly 2% of those found to have artery build-up, the atherosclerosis was even more severe. Blood flow was obstructed to the main artery that supplies blood to large portions of the heart, and in some cases, all three coronary arteries were obstructed. Atherosclerosis started an average of 10 years later in women compared to men. Atherosclerosis was 1.8 times more common in people ages 60-64 vs. those ages 50-54. Participants with higher levels of atherosclerosis seen by CCTA also had higher CAC scores. Of those with a CAC score of more than 400, nearly half had significant blockage, where more than 50% of the blood flow was obstructed in one of the coronary arteries. In those with a CAC score of zero, 5.5% had atherosclerosis detected by CCTA, and 0.4% had significant obstruction of blood flow.

The ability to study and compare organ aging in the context of organismal aging has recently been documented using a geropathology approach. This concept consists of identifying and grading age-related histopathologic lesions so that a quantitative score is established for each organ allowing for comparison of lesion scores between all organs examined and between all animals in a specific cohort. Therefore, the contribution of each organ to aging can be assessed, in contrast to studying the effect of aging or age-related disease on each organ.

Geropathological interrogation of individual organs provides a powerful look at the morphologic changes associated with increasing age in an organ-dependent manner. For example, based on severity of age-related histopathologic lesion scores, it can be seen that different organs age at different rates with increasing age in C57BL/6 and CB6F1 mice. The heart ages earlier and more rapidly in CB6F1 mice from 8 months to 24 months compared to C57BL/6 mice. Surprisingly, there is no difference in aging of the lungs across this age span in the two strains. For the liver, age-related lesions are seen 8 months earlier in C57BL/6 mice and there is an increase in aging in C57BL/6 mice from 16 to 32 months. The pattern was similar for the kidney, with age-related lesions occurring earliest in C57BL/6 mice at 16 months and then progressing more rapidly.

The second example provides insight into how different organs respond to therapeutic drugs based on changes in severity of lesion scores. Studies with C57BL/6 mice treated for 3 months starting at 20 months of age have shown that organ response based on lesion scores is drug dependent in four major organs- heart, lungs, liver and kidney. For rapamycin, an mTOR inhibitor, kidney, heart and liver were most responsive in males but only kidney was responsive in females using a dose of 14 ppm in the feed. For acarbose, an antidiabetic drug, heart and kidney were most responsive in both genders at a dose of 1000 ppm in the feed. For phenyl butyric acid, an inhibitor of histone deacetylation, lungs and kidney were most responsive in both genders at a dose of 1000 ppm in the feed. In addition, published observations for fisetin, a natural product with senolytic activity, have shown lungs and kidney to be most responsive. It is worth noting that the kidney appears to be less drug dependent, suggesting it might serve as a sentinel organ in drug studies investigating effects on aging, at least in C57BL/6 mice of both genders. These types of observations will be invaluable for helping make decisions on selection of effective drug combinations for aging intervention studies.

One of the most impactful and reproducible interventions that can slow down age-associated pathologies is calorie restriction (CR). CR is an intervention to prolong longevity, where the number of calories consumed is decreased but sufficient nutrition is maintained. Initially seen in a rodent study in 1935, recent findings have demonstrated its beneficial effect in mammals and primates. It has been thought that these advantages are mediated through stem cell proliferation and perseveration of stem cell activity, thus functioning as a regenerative therapy. Therefore, a thorough understanding of the mechanism, regulation, and signalling molecules underlying the advantages of CR for specific stem cells, such as muscle stem cells, intestinal epithelium stem cells, hematopoietic stem cells (HSCs) and hair follicle stem cells, would help in determining specific pharmacological and dietary intervention for regenerative therapy in the future. In addition, the structural and functional modifications observed can provide a more complete understanding of the numerous CR effects and thus be useful in therapy consideration.

One of the characteristics seen in age-related pathologies is stem cell exhaustion. Here, we review the various impacts of CR on mammalian health mediated through stem cell potency in various tissues. In the skeletal muscle, CR acts as an anti-inflammatory agent and increases the presence of satellite cells endogenously to improve regeneration, thus causing a metabolic shift to oxidation to meet oxygen demand. In the intestinal epithelium, CR suppresses the mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells to shift the stem cell equilibrium towards self-renewal at the cost of differentiation. In haematopoiesis, CR prevents deterioration or maintains the function of HSCs depending on the genetic variation of the mice. In skin and hair follicles, CR increases the thickness of the epidermis and hair growth and improves hair retention through stem cells. CR mediates the proliferation and self-renewal of stem cells in various tissues, thus increasing its regenerative ability.

When cells begin to turn cancerous, they start producing mutated proteins not seen in healthy cells. These cancerous proteins, also called neoantigens, can alert the body's immune system that something has gone wrong, and T cells that recognize those neoantigens start destroying the cancerous cells. Eventually, these T cells experience a phenomenon known as "T cell exhaustion," which occurs when the tumor creates an immunosuppressive environment that disables the T cells, allowing the tumor to grow unchecked.

Scientists hope that cancer vaccines could help to rejuvenate those T cells and help them to attack tumors. In recent years, they have worked to develop methods for identifying neoantigens in patient tumors to incorporate into personalized cancer vaccines. Some of these vaccines have shown promise in clinical trials to treat melanoma and non-small cell lung cancer. "These therapies work amazingly in a subset of patients, but the vast majority still don't respond very well. A lot of the research in our lab is aimed at trying to understand why that is and what we can do therapeutically to get more of those patients responding."

Previous studies have shown that of the hundreds of neoantigens found in most tumors, only a small number generate a T cell response. Now a new study helps to shed light on why that is. In studies of mice with lung tumors, the researchers found that as tumor-targeting T cells arise, subsets of T cells that target different cancerous proteins compete with each other, eventually leading to the emergence of one dominant population of T cells. After these T cells become exhausted, they still remain in the environment and suppress any competing T cell populations that target different proteins found on the tumor. However, researchers found that if they vaccinated these mice with one of the neoantigens targeted by the suppressed T cells, she could rejuvenate those T cell populations. "If you vaccinate against antigens that have suppressed responses, you can unleash those T cell responses. Trying to identify these suppressed responses and specifically targeting them might improve patient responses to vaccine therapies."

Neurodegenerative disease defines conditions in which there is progressive neuronal loss in the central nervous system (CNS), leading to either physical disability, cognitive deficits or both. Classical neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Aging is a major risk factor for neurodegenerative disease, and with a growing elderly population, its prevalence is continuously increasing. Beyond being a risk factor, aging also increases the severity of disease and results in an impaired recovery following insult. Although these diseases have different pathogenetic mechanisms such as protein aggregation, demyelination, ischaemia, or direct trauma, they all share a hallmark of neuroinflammation.

The immune system plays a key role in CNS homeostasis and disease. The innate immune system is the first line of defense against pathogens and central nervous system (CNS)-resident macrophages, microglia, are of vital importance as early respondents to CNS alterations such as damage or infection but also in development and homeostasis. Microglia activation is also an important component of neuroinflammation, aging, and different neurodegenerative diseases either directly via phagocytosis and cytokine production, as shown by the identification of disease-specific microglia, or indirectly in response to cues from the adaptive immune system.

The adaptive immune system is an important component of the host defense against pathogens, through the recognition of non-self antigens. This defensive mechanism is mediated by B lymphocytes and T lymphocytes which display a diverse range of specific antigen receptors during humoral and cellular-mediated immunity. Although the CNS was once considered an 'immune-privileged' site, recent studies have indicated the presence and importance of the adaptive immune system in the CNS for immune-surveillance and defense against neurotropic viruses. Studies have also highlighted the role of adaptive immunity in maintaining CNS homeostasis and integrity, promoting neurogenesis and improving cognitive function.

In healthy individuals, this immune-CNS interaction is highly regulated to maintain the beneficial relationship. However, during both aging and neurodegenerative disease, the blood-brain barrier (BBB) is disrupted, leading to an increased infiltration of peripheral immune cells into the CNS, where they can potentiate further neurodegeneration or facilitate tissue regeneration. In both neurodegenerative disease and the normal aging process, there is a common theme of immune dysregulation and abnormal immune responses.

Senescence is a cell state that contributes to several homeostatic and pathological processes. In addition to being induced in somatic cells in response to replicative exhaustion (replicative senescence, RS) as part of organismal aging, senescence can also be triggered prematurely by oncogene hyperactivation or tumor suppressor dysfunction (oncogene-induced senescence, OIS). Consequently, senescent cells comprise a major component of precancerous lesions of skin, oral mucosa, nasopharynx, prostate, gut, and lung.

Unfortunately, invasive (or minimally invasive) interventions are currently the only available approach employed to eradicate premalignant lesions that carry the potential for cancer progression. Oncogene-Induced Senescence (OIS) is one form of senescence that occurs in response to oncogene overexpression in somatic cells and is present in precancerous lesions. While the contribution of OIS to disease progression is undetermined, recent evidence suggests that senescent cells are permissive for malignant transformation.

Senolytics are a newly emerging drug class capable of selectively eliminating senescent cells. While senolytics have been successfully demonstrated to mitigate a myriad of aging-related pathologies and to cull senescent cancer cells, there is a paucity of evidence for the potential use of senolytics as a novel approach to eliminate oncogene-induced senescent cells. This commentary will: (i) summarize evidence in established models of OIS including B-Raf-induced nevi, transgenic lung cancer, and pancreatic adenocarcinoma models as well as evidence from clinical precancerous lesions; (ii) suggest that OIS is targetable; and (iii) propose the utilization of senolytic agents as a revolutionary means to interfere with the ability of senescent premalignant cells to progress to cancer in vitro and in vivo. If proven to be effective, senolytics will represent an emerging tool to pharmacologically treat precancerous lesions.

We argue that some of the key principles of particle physics can be borrowed to study biological systems that age. Namely, these principles are: (a) Every interaction leads to a transformation of all interacting subjects. (b) Every process can be dissociated from the chronological time and considered as a sequence of discrete events. It is the order and the number of these events that predetermines the outcome, not time. (c) The threshold value is predetermined by a probability for a specific interaction to cause a specific transformation. An at-the-threshold event occurs not because of the accumulation of prior stimuli but because an increasing number of stimuli increased the probability of the observed event.

These principles can help understand the nature of aging or other biological processes. Cell functionality is determined by complex interactions of atoms within micro- and macromolecules with various cell structures and internal cell environments. During aging, discrete transformations in a cell eventually negatively affect cell system functionality. When atoms within molecules change their characteristics due to interactions and transformations, such as radioactivity, oxidation, reduction, etc., the macromolecule's whole functionality is altered. Alteration of functionality causes direct damage to a system by performing an alternative function or indirect damage defined by a loss of functionality.

In other words, systematic damage accumulation from the standpoint of a whole system leads to the decay of the system. Once damage in a system reaches a certain magnitude i.e. reaches a threshold, the system stops performing the originally designated function. When a cell can no longer maintain critical functionality, it finally transforms into a highly non-functional state. On an organism level, outcomes can look differently, e.g., senescence, cancer, coronary diseases, diabetes.

Therefore, biological aging may be defined as a sequence of highly discrete transformations caused by a combination of internal and external factors that lead to chronic damage accumulation and the consequent loss of functionality of a system. The transformations of damage repair mechanisms themselves may lead to their reduced functionality, representing critical thresholds since it would increase the rate of damage accumulation. However, some systems also exist where damage dilution, partitioning, clearance, decay and/or pre-emption support cell rejuvenation, thereby making the biological system appearing as non-aging (e.g. immortalized mammalian cell lines, germline, hydra).

Lobsters are notoriously difficult to age. Nobody knows exactly how old they can get, and some experts have estimated they could live on the ocean floor for as long as a century or more. "Until now, a lobster's age has usually been estimated using its size - but this is inaccurate as individual lobsters grow at different rates. For a long time, it appeared that there was no accurate way to quantify a lobster's age. Some research suggested that you could tell a lobsters age by counting the rings in parts of their eyestalks and stomach - a little like counting tree rings. But you can't do that for a living lobster."

"Lobsters have hard, inelastic shells and so in order to grow they must shed their old shell and replace it with a new one. However, lobsters of the same age don't always grow and moult at the same time. For example, lobsters with more food or in warmer waters can grow more quickly, which makes it really hard to know how old lobsters actually are. It is crucial to be able to estimate how many lobsters of particular ages are present in a given area so that they can be sustainably harvested. We wanted to develop a new, non-lethal method of determining the age of European lobsters that could be of better use for lobster fisheries management. The European lobster was an ideal species to study because it is economically and ecologically very important."

The research team used a method that relies on quantifying epigenetic changes that accumulate with age within a lobster. Lobsters raised from eggs, so that the exact ages of individuals was known, allowed the researchers to calibrate their methods. "We identified a very strong relationship between age and epigenetic modifications, which allowed us to accurately estimate the ages of individual lobsters. Applying this method to wild lobsters predicted ages that generally aligned with minimum estimates of age based on size."

Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed "next-generation clock" DNAmGrimAge outperforms "first-generation clocks" in predicting longevity and the onset of many age-related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm-based biomarker of healthy aging.

A fundamental biological property of epigenetic modifications, in particular DNAm, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the "Diet, Physical Activity, and Mammography" (DAMA) study: a 24-month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial.

Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer-related pathways. There was no significant slowing of DNAmGrim associated with the physical activity intervention nor reduced EML associated with the dietary intervention. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging-related epigenetic mechanisms.

Cerebral small vessel disease (SVD) is a leading cause of cognitive decline and functional loss in the elderly. Cerebral SVD is recognised by the resultant parenchymal lesions rather than the underlying small vessel alterations themselves, and typically manifests as lacunar lesions, diffuse white matter lesions (leucoaraiosis) and/or microbleeds. Accordingly, cerebral white matter hyperintensities (WMH) on MRI scan are recognised surrogates of cerebral SVD. Although the aetiopathogenic mechanisms of cerebral SVD are unclear, there is a clear distinction from cerebral large vessel disease. Indeed, with the exception of hypertension, conventional cardiovascular risk factors such as diabetes and hyperlipidaemia have inconsistent correlation with cerebral SVD. Further, after accounting for age and the traditional vascular risk factors, much of the variance in WMH volume remains unexplained.

Cerebral WMH predict incident stroke, dementia, heart failure, disability, and mortality. Despite the lack of correlation with conventional cardiovascular risk factors and with no supporting evidence base, current treatment strategies for managing cerebral WMH are extrapolated from the general management guidelines for the treatment of atherosclerotic disease. As a result, treatment strategies focusing on the use of antiplatelet, statins, aggressive blood pressure (BP) lowering and (in people with diabetes) aggressive glycaemic control may not be effective in the treatment of cerebral SVD. The absence of specific treatments for cerebral SVD precipitates the need for clear targets or strategies for the treatment of cerebral SVD.

We propose the search for such targets should focus on the underlying pathology of cerebral SVD, focusing specifically on the regulation of cerebral microcirculation. However, in order to identify potential treatment strategies, knowledge of the systemic correlates of cerebral SVD is required. As WMH are present in patients with and without history of previous CVD, we aimed to explore this in a general population sample of older adults enriched with patients with proven cerebral SVD.

Several studies have shown that obesity is a risk factor for numerous diseases, including diabetes mellitus, hypertension, coronary artery disease, stroke, fatty liver disease, sleep-disordered breathing, mental health, and cancer. Obesity has also been shown to be closely related to all-cause mortality. Several observational studies revealed that obesity could accelerate the aging process. Moreover, a meta-analysis indicated that people with extreme obesity may have a reduced life expectancy by about 14 years. However, there is little evidence on the causal relationship between genetic influence of visceral adipose tissue (VAT) accumulation and longevity.

Mendelian randomization (MR) analysis is a useful approach for estimating the causal relationship between an exposure factor and outcome based on observational data from genome-wide association studies (GWASs). Single-nucleotide polymorphisms (SNPs) typically serve as the instrumental variables for investigating the causal role of an exposure factor on a disease or disease-related outcome. A valid instrumental variable is one that is (1) associated with the exposure, (2) independent of confounders, and (3) independent of the outcome conditional on the exposure and confounders. In this two-sample MR analysis, we employed the genetic variants (SNPs) of VAT accumulation as instrumental variables to explore the causal relationship with longevity.

Our MR analysis used 221 genetic variants as instrumental variables to explore the causal association between VAT accumulation and longevity. VAT accumulation (per 1-kg increase) was found to be significantly associated with lower odds of surviving to the 90th (odds ratio [OR] = 0.69) and 99th (OR = 0.67) percentile ages. This MR analysis identified a causal relationship between genetically determined VAT accumulation and longevity, suggesting that visceral adiposity may have a negative effect on longevity.