Fight Aging!

Fibrosis is the excessive deposition of extracellular matrix, forming scar-like structures that are disruptive to tissue function. It is a feature of aging in many organs, such as heart, liver, kidney, and lungs, and when particularly pronounced it is declared to be fibrotic disease. So far medical science has struggled to make much headway in the reversal of fibrosis once it is established, which makes these conditions particularly threatening.

Fibrosis is connected to the chronic inflammation characteristic of old age, and in recent years evidence has amassed for senescent cells to drive fibrosis. Senescent cells increase in number with age in tissues throughout the body, and produce pro-growth, pro-inflammatory signaling. When tissue is injured, senescent cells emerge for a short time to help coordinate regeneration. In later life, this constant signaling alters cell behavior for the worse, disrupting normal tissue maintenance to encourage pathologies like fibrosis to develop.

Selectively clearing senescent cells via the use of senolytic drugs has been shown in animal studies to reverse fibrosis in a number of different organs. One of the first small human clinical trials of senolytic drugs targeted patients with idiopathic pulmonary fibrosis. It is this condition, and the senescent cells that may drive its onset and development, that are the subject of today's open access review paper.

Molecular mechanisms of alveolar epithelial cell senescence and idiopathic pulmonary fibrosis: a narrative review

Idiopathic pulmonary fibrosis (IPF) is a commonly diagnosed chronic, progressive, and fibrotic interstitial pneumonia that accounts for 20-30% of interstitial lung diseases. It usually occurs in middle-aged and elderly individuals. It is now generally accepted that persistent alveolar epithelial damage and repair dysregulation are the principal mechanisms leading to progressive pulmonary fibrosis.

Repetitive epithelial cell injury and deficiencies in regeneration result in the release of mediators, including cytokines, chemokines, fibrogenic factors, coagulant proteins, oxidants, and regulators of apoptosis. This leads to the recruitment, proliferation, and activation of interstitial fibroblasts to form fibrotic foci. Additionally, excessive deposition of the extracellular matrix leads to destruction of lung parenchymal structures. Interestingly, a variety of cells, including alveolar epithelial type II cells (ATII) and fibroblasts, can drive IPF. Regardless of the driver cell types, senescence leads to a decrease in the repair capacity of damaged alveolar epithelium. As a result, fibrous tissue replaces the damaged alveolar epithelium.

From a histopathological point of view, IPF formation is a dynamic process involving complex interactions among epithelial cells, fibroblasts, immune cells (such as macrophages and T lymphocytes), and endothelial cells. Alveolar epithelial cells undergo cytoskeletal remodeling and acquire a mesenchymal phenotype through epithelial-mesenchymal transition (EMT), in which epithelial cells lose intercellular attachment, polarity, and epithelial-specific markers, leading to fibrosis.

Some investigators have identified ATII as a major player in the synthesis of transforming growth factor-beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) in lung biopsies from patients with IPF. In the process of organ fibrosis formation, including pulmonary fibrosis, TGF-β acts as the master switch for the induction of the EMT process. In particular, TGF-β mediates fibrous proliferative effects by inducing apoptosis in alveolar epithelial type I (ATI) cells. However, there is no direct evidence that TGF-β promotes IPF by inducing senescence in the alveolar epithelial cells.

In the lungs of patients with IPF, the ability of ATII cells to transdifferentiate into ATI cells is diminished. Emerging evidence also suggests that triggering ATII senescence can promote IPF. Therefore, studying the mechanisms of cellular senescence in the lung microenvironment is crucial to understand IPF pathogenesis and progression. Decreasing senescent alveolar epithelial cells may be a promising strategy for the treatment of IPF. Therefore, further investigations into new treatments of IPF by applying inhibitors of relevant signaling pathways, as well as senolytic drugs, are warranted.

It remains the case that all too little in medical science is demonstrated to be better than exercise for improved long-term health. Much of the early work on ways to slow aging, pioneered by the supplement industry, has proven to be less effective than structured exercise programs when finally evaluated in clinical trials. One conclusion is that the research and development communities must do better, aim higher. Another conclusion, the subject of this open access paper, is that perhaps the practicing medical community should become much more serious about exercise.

Lack of exercise is a health concern worldwide. According to WHO, 31% of the world's population does not attain the minimum required level of physical activity. This unhealthy lifestyle is the fourth leading cause of death worldwide with approximately 3.2 million deaths annually. This situation is continuously worsening and poses a substantial burden on health systems and societies. A considerable portion of health conditions can be attributed to physical inactivity. Sedentary behavior and physical inactivity are the leading risk factors for cardiovascular disease and all-cause mortality. Compared with people who have previously been physically active, those who are inactive have a higher risk of developing neurological diseases.

Recognizing that many chronic diseases are closely related to poor lifestyle habits and that exercise plays a role in a variety of health conditions, the American College of Sports Medicine and the American Medical Association suggested that "exercise is medicine". Subsequently, a multinational collaboration on "exercise is medicine" began and this initiative was centered on global awareness. In this initiative, it was suggested that patients' level of physical activity be added to their medical records, and behavioral physical activity counseling should be provided through a clinical decision support system.

Specifically, the exercise situation of each patient should be considered as a vital sign in each visit, then healthcare workers should provide professional physical activity guidance for patients' exercise situation and health needs. This initiative emphasized that exercise should be used as medical advice in clinical settings. Hence it is not just improving patients' exercise awareness that is significant, but more so the formation of normative medical work for exercise guidance and the healthcare workers' awareness of exercise effects in health.

Link: https://doi.org/10.3389/fnagi.2023.1129221

Naked mole-rats exhibit few signs of aging across a life span. Only the queens bear young, but they can continue do so into old age. As this study notes, they achieve this feat via a number of mechanisms that ensure a continued supply of egg cells. This isn't just a matter of minimizing damage to these cells and their supporting tissues, but also generating new egg cells in adult life, unlike other mammals. It remains an open question as to whether there is any great realization yet to be found in this comparative biology that will benefit efforts to extend human fertility into later life. It doesn't hurt to look.

Unlike humans and other mammals, which become less fertile with age, naked mole-rats can reproduce throughout their remarkably long lifespans. For most mammals, including humans and mice, females are born with a finite number of egg cells, which are produced in utero via a process called oogenesis. Because this limited supply of egg cells depletes over time - some are released during ovulation, but most simply die - fertility declines with age. In contrast, naked mole-rat queens can breed right through old age, suggesting the rodents have special processes to preserve their ovarian reserve and avoid waning fertility. "There are three possibilities for how they do this: They are born with a lot of egg cells, not as many of these cells die, or they continue to create more egg cells after birth. My favorite hypothesis is that they use a cocktail of all three." Sure enough, researchers found evidence for each of the three processes.

The researchers compared ovaries from naked mole-rats and mice across different stages of development. Despite their similar sizes, mice live four years at most and start to show a drop in fertility by nine months, whereas naked mole-rats have a life expectancy of 30 years or more. They found that naked mole-rat females have exceptionally large numbers of egg cells compared to mice and that death rates of these cells were lower than in mice. For example, at 8 days old, a naked mole-rat female has on average 1.5 million egg cells, about 95 times more than mice of the same age. Most remarkably, the study found that oogenesis happens postnatally in naked mole-rats. Egg precursor cells were actively dividing in 3-month-old animals, and these precursors were found in 10-year-old animals, suggesting that oogenesis could continue throughout their lives. 

Link: https://www.upmc.com/media/news/022123-naked-mole-rat-fertility

Calorie restriction is known to slow aging, albeit to a much greater degree in short-lived species than in long-lived species. Finding important mechanisms involved in the beneficial response to calorie restriction continues to be a major focus on the research community, even though it is questionable as to whether this is a good approach to the treatment of aging. A sizable fraction of the response to calorie restriction appears to be mediated by methionine sensing, at least judging by the degree to which reducing methioninine intake can reproduce the benefits of full calorie restriction.

In today's open access paper, researchers connect NANOG expression to the methionine restriction response, certainly an interesting link. NANOG is a pluripotency factor expressed in embryonic stem cells, studied in the contexts of regeneration, cancer, and cell reprogramming. One might not expect it to employ methionine sensing mechanisms to achieve changes on cell metabolism, and yet it does. Everything connects to everything else when it comes to regulation of cell behavior, it seems.

More pertinently, senescent cells are metabolically active, with a high methionine metabolism driving their ability to generate harmful signaling. Expressing NANOG squashes that activity to restore better function. This is perhaps a good idea in severe conditions such as progeria in which a sizable fraction of cells become senescent, but less of a good idea in normal aging, even given a role of cellular senescence in the onset of age-related disease, given the balance between NANOG expression and risk of cancer.

Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle

A recent study demonstrated that a methionine-restricted (MR) diet improved mitochondrial function and upregulated autophagy-related genes, resulting in a 45% extension of rodent lifespan. Other studies also demonstrated that MR regulates energy expenditure in the aged musculoskeletal system, activated insulin signaling that improved type II diabetes, and decreased lipid peroxidation that reduced hyperlipidemia. Clearly, decreasing dietary methionine has beneficial physiologic effects. However, a pathway connecting methionine to these pathologies is yet to be elucidated. Methionine breakdown begins with MAT2A, which catalyzes the production of S-adenosyl methionine (SAMe) from methionine.

Previously, our laboratory reported similar pathologies affecting cells from progeria patients and cells undergone replicative senescence. Further, we demonstrated that with ectopic expression of the pluripotency factor, NANOG could effectively reverse aging hallmarks and reestablish young attributes in older cells to restore their myogenic differentiation capacity, decrease senescence-associated beta-galactosidase (SA-βgal), restore mitochondrial function, and repair DNA damage. NANOG also restored the ability of senescent myoblasts to differentiate into healthy skeletal myotubes and ameliorated the hallmarks of cellular senescence including genomic instability, loss of proteostasis, and mitochondrial dysfunction in human skeletal myoblasts and restored the number of myogenic progenitors in a mouse model of premature aging.

However, the mechanism through which NANOG imparts its rejuvenating effects is not known. Using NANOG as an investigative tool, we examined whether metabolic impairments due to senescence or premature aging could be reversed, restoring muscle function. We discovered that senescent myoblasts used methionine to meet their metabolic demands and that increased use of methionine contributed to the loss of skeletal muscle function. Conversely, inhibition of MAT2A catabolism by NANOG expression or chemical inhibition restored glucose-based bioenergetics and the force-generating capacity of aged skeletal muscle in a mouse model of premature aging.

A range of evidence suggests high intensity exercise to produce different, greater benefits than is the case for more moderate, longer periods of exercise. Researchers here look at the biochemistry of cellular senescence in muscle tissue immediately following exercise, and find the characteristics notably different. The results suggest that high intensity exercise induces more short-term inflammatory cell stress, but removes more of the pre-existing markers of cellular senescence as a result of a greater immune reaction to that stress.

In this study, we asked the question whether the cellular senescence-lowering effect of exercise in human skeletal muscle can occur only at the intensity sufficient to induce DNA damage and inflammation. Biopsied vastus lateralis of 9 sedentary men (age 26.1 ± 2.5 y) were assessed before and after a single bout of moderate steady state exercise (SSE, 60% maximal aerobic power) and high intensity interval exercise (HIIE, 120% maximal aerobic power). Increases in cell infiltration (+1.2 folds), DNA strand break (+1.3 folds), and γ-H2AX+ myofibers (+1.1 folds) occurred immediately after HIIE and returned to baseline in 24 hours. Muscle p16Ink4a mRNA decreased 24 hours after HIIE. SSE had no effect on cell infiltration, p16Ink4a mRNA, and DNA strand break in muscle tissues.

The major findings are as follows: (1) Cellular senescence-lowering effect of aerobic exercise can occur only at high intensity. SSE with similar exercise work failed to lower the p16INK4a mRNA in human skeletal muscle within the 24-h recovery period; (2) HIIE triggered immediate increases in cell infiltration and γ-H2AX+ myofibers, followed by a decreased p16INK4a mRNA in human skeletal muscle 24 hours after recovery; (3) By further examining the individual responses, the senolytic effect of HIIE were contributed solely from those participants with high pre-exercise p16INK4a mRNA in skeletal muscles.

High intensity exercise is known to cause greater levels of lactate production and acidosis than low intensity exercise. Decreased pH has been reported to be a danger signal to activate innate immune response and immune cells are functioned to recognize and clear senescent cells by phagocytosis in humans. Therefore, the acute changes in the microenvironment during and after exercise may be a selection pressure to aged stem cell population resided in the skeletal muscle. Exercise intensity determines the magnitude of cell renewal during a brief period of inflammation.

Taken together, decreased cellular senescence 24 hours after HIIE is best explained by senescent cell clearance following a brief increase of bone marrow cell infiltration into challenged skeletal muscle to participate in the early phagocytic and late regenerative phases of inflammation. DNA damage is a potent stimulator of inflammation. In this study, a fast resolution of DNA damage/repair response 24 hours following HIIE suggests an efficient clearance of senescent cells with DNA damage in human skeletal muscle to resolve the inflammation.

Link: https://doi.org/10.18632/aging.204511

Can one replace parts of the brain? In principle, yes. It is a tissue, and tissue engineering is a field intent on regrowth and replacement of lost or damaged tissue. There are parts of the brain immediately vital to life, and parts that hold the memory that defines the self; if those are lost, that is irrecoverable. But much of the brain might be tissue engineered in the same way as muscle or liver might be replaced. Researchers are still in the early stages of the long road towards replacement tissues created to order, as illustrated by the scientific work noted here, but much of the brain will be a part of that field of development.

The transplantation of pluripotent stem cell-derived neural precursors into the cortex is an exciting potential approach to repair the brain. To achieve this goal, grafted cells must re-establish damaged neural circuits that participate in the restoration of lost behavioral function. Significant progress has been made in demonstrating the feasibility of transplanting precursor cells to replace neurons in the cortex. Graft-derived neurons can survive for years in mice and differentiate into appropriate neuronal subtypes that exhibit normal electrophysiological activity, project long distances outside of the graft to appropriate targets, synaptically integrate with surrounding host neurons, and respond to sensory input and participate in motor output.

Despite these significant discoveries, it is unclear whether grafted neurons in the neocortex can encode useful behavior as a result of their electrophysiological activity. Reported behavioral benefits are instead a result of activity-independent functions such as the secretion of anti-inflammatory or neurotrophic factors. The inability to demonstrate that electrophysiological activity of grafted neurons encode useful behavior is not surprising considering there are cortical cell types that are thus far missing in grafts, in addition to these grafts lacking normal cortical cytoarchitecture. While cerebral organoids display a subset of similar characteristics to a normal fetal cortex, their differentiation has thus far been abnormal after transplantation. Therefore, there is currently no method of generating facsimiles of neocortical tissue in adults, whether for the purpose of study or therapy.

The goal of this study is to provide an initial proof of concept for a neocortical grafting platform that supports (1) the survival and differentiation of the major neocortical cell types, (2) vascularization, (3) neuronal integration, and (4) layering. Toward this goal, we tested whether grafting cells in a three-dimensional scaffold could sustain the differentiation of all the major cortical cell types, vascularization, and a layered cytoarchitecture. Using dissociated mouse cortical fetal cells mixed with a commercial scaffold, we found that the neuronal, glial, and vascular components within the graft survived and successfully integrated with the host tissue. Our results suggest that this platform is suitable for future optimization and testing of structured, vascularized, multi-cell type neocortical tissue prototypes.

Link: https://doi.org/10.3390/bioengineering10020263

It is the nature of becoming older that diverse and quite different age-related conditions proceed in parallel, linked by the contributions of shared underlying mechanisms, such as chronic inflammation, or mitochondrial dysfunction. Individuals age at different rates, largely the result of lifestyle choices and environmental factor such as exposure to persistent pathogens such as herpesviruses. In any given individual, however, different aspects of aging often appear correlated, as they are the results of deeper processes of damage and dysfunction.

The thymus is a small organ in which thymocytes produced in the bone marrow mature into T cells of the adaptive immune system. Active thymic tissue is slowly replaced with fat over later life, and the declining production of new T cells contributes to the age-related dysfunction of an immune system consisting ever more of worn, exhausted, malfunctioning, and senescent cells. Chronic kidney disease is most often a downstream consequence of diabetes and/or raised blood pressure, but rising numbers of senescent cells in older individuals are implicated in the fine details of its pathology, such as fibrosis, the production of scar-like excess collagen deposition that is disruptive of tissue structure and function.

Consider a correlation between the degree of thymic involution and the severity and progression of chronic kidney disease. These are very different issues, but both impacted by mechanisms such as the chronic inflammatory signaling characteristic of old age. In today's open access paper, researchers present data illustrating this correlation in a study population with chronic kidney disease. Correlation doesn't necessarily imply any direction of causation; both issues might contribute to the other, or be more independent outcomes of shared underlying mechanisms. The researchers here favor the idea that immune dysfunction contributes to a worsened progression of chronic kidney disease, however.

Decreased thymic output predicts progression of chronic kidney disease

In this study, we explored the impact of T cell senescence on the renal prognosis and mortality of patients with chronic kidney disease (CKD). We found that decreased recent thymic emigrant (RTE) T cells, which corresponds to decreased thymic output, was associated with CKD progression and high mortality, and an increase in highly differentiated CD28-CD4+ T cells, which increases with age, tended to be associated with CKD progression. Thymic atrophy is a characteristic of an aging immune system and has been implicated in age-related diseases such as infection, malignancy, atherosclerosis, and CKD. However, epidemiologic data are limited in patients with non-dialysis-dependent CKD. To our knowledge, this is the first study to demonstrate the impact of decreased thymic output on renal prognosis and all-cause mortality in patients with non-dialysis-dependent CKD.

An immunological model has been constructed using epidemiological and immunological data to show that an age-related decrease in thymic output is associated with the development of infectious diseases and malignancies. Decreased RTE in renal transplant patients increases all-cause mortality. In dialysis patients, decreased RTE is associated with death caused by infection, and decreased naive T cell count due to thymic atrophy increase all-cause mortality. Furthermore, our results are consistent with previous findings showing that shorter telomeres in peripheral blood leukocytes worsen renal prognosis and mortality, because the decrease in naive T cell counts due to thymic atrophy is compensated by increased T cell division, thereby shortening telomeres.

There are three potential mechanisms by which decreased thymic output contributes to CKD progression and increased mortality. (a) Low thymic output reduces the diversity of TCR repertoire and may reduce the clearance of senescent cells by immune cells. (b) When the number of newly produced naive T cells decreases, homeostatic proliferation maintains the peripheral T cell count. However, homeostatic proliferation increases the percentage of dysfunctional memory-type T cells in mice. These T cells secrete inflammatory chemokines involved in chronic tissue inflammation, delay kidney tissue repair after acute kidney injury, and may be associated with CKD progression. (c) Thymic atrophy may reflect a systemic state of aging. As aging progresses, local and systemic inflammation induced by senescent-associated secretory phenotype (SASP) causes organ damage, which may cause thymic atrophy and decreases kidney function, and increase mortality. Conversely, the presence of CKD decreases thymic output, increasing the susceptibility to further progression of CKD and high mortality.

Researchers here note that a number of cellular quality control mechanisms exhibit better function in centenarians than in the average elderly population. It is thought that the various systems responsible for quality control of proteins, such as autophagy, decline in function with advancing age. Given this, it is perhaps to be expected that centenarians exhibit a slower reduction in this capacity than their peers. In order to become centenarians, these individuals must necessarily be less impacted by aging, less damaged, less dysfunctional.

We have shown before that at least one intracellular proteolytic system seems to be at least as abundant in the peripheral blood lymphocytes of centenarians as in the same cells of young individuals (with the cells of the elderly population showing a significant dip compared to both young and centenarian cohorts). Despite scarce published data, in this review, we tried to answer the question how do different types of cells of longevous people - nonagenarians to semi-supercentenarians - maintain the quality and quantity of their structural and functional proteins? Specifically, we asked if more robust proteodynamics participate in longevity.

We hypothesized that at least some factors controlling the maintenance of cellular proteomes in centenarians will remain at the "young" level (just performing better than in the average elderly). In our quest, we considered multiple aspects of cellular protein maintenance (proteodynamics), including the quality of transcribed DNA, its epigenetic changes, fidelity and quantitative features of transcription of both mRNA and noncoding RNAs, the process of translation, posttranslational modifications leading to maturation and functionalization of nascent proteins, and, finally, multiple facets of the process of elimination of misfolded, aggregated, and otherwise dysfunctional proteins (autophagy). We also included the status of mitochondria, especially production of ATP necessary for protein synthesis and maintenance.

We found that with the exception of the latter and of chaperone function, practically all of the considered aspects did show better performance in centenarians than in the average elderly, and most of them approached the levels/activities seen in the cells of young individuals.

Link: https://doi.org/10.3390/ijms24032888

Researchers here discuss an investigation of the role of hydrogen sulfide in cell function and long-term health. Upregulation of hydrogen sulfide levels is an approach to modifying metabolism in order to modestly slow aging, and researchers here note an overlap with the mechanisms of calorie restriction, in that low nutrient levels increase the production of hydrogen sulfide in the body. While scientifically interesting, this sort of intervention is hardly the way forward to meaningfully extend the healthy human life span. We need better, more targeted approaches that do more to directly reverse the damage and dysfunction of aged tissues.

The molecular determinants of lifespan can be examined in animal models with the long-term objective of applying what is learned to the development of strategies to enhance longevity in humans. Here, we comment on a recent publication examining the molecular mechanisms that determine lifespan in worms, Caenorhabditis elegans (C. elegans), where it was shown that inhibiting protein synthesis increased levels of the transcription factor, ATF4. Gene expression analyses showed that ATF4 increased the expression of genes responsible for the formation of the gas, hydrogen sulfide (H2S).

Further examination showed that H2S increased longevity in C. elegans by modifying proteins in ways that stabilize their structures and enhance their functions. H2S has been shown to improve cardiovascular performance in mouse models of heart disease, and clinical trials are underway to test the effects of H2S on cardiovascular health in humans. These findings support the concept that nutrient deprivation, which slows protein synthesis and leads to ATF4-mediated H2S production, may extend lifespan by improving the function of the cardiovascular system and other systems that influence longevity in humans.

Link: https://doi.org/10.20517/jca.2022.16

Cellular biochemistry is a messy process, a soup of colliding molecules moving at high speed and reacting with one another. Within this soup, complex processes of assembly and interaction take place. The blueprints of genes in DNA are converted into RNA via one complicated set of reading and assembly mechanisms in the cell nucleus. That RNA exits the nucleus and is then processed in ribosomes to produce proteins from amino acid fragments. Proteins are then folded in to the correct shape in the endoplasmic reticulum, and then must further be transported to a final destination within the cell.

All of this takes place within a dense storm of fast-moving molecules of all sorts, and any number of inappropriate interactions and reactions. Quality control is important, as all of the processes mentioned above can fail. Errant proteins and damaged structures are promptly identified and removed, broken down into amino acid fragments for recycling. Evolution has produced a system of assembly and quality control that has a high fidelity, suggesting that it is important for cell and tissue function for protein manufacture to produce few errors. But are variations in error rate an important contribution to differences in life span between species?

Thermophiles reveal the clues to longevity: precise protein synthesis

During the lifetime of an organism, proteins are constantly exposed to stressors that impair their function. Protein homeostasis networks have evolved to monitor and regulate the synthesis, folding, trafficking, and degradation of proteins. The earliest process in the protein life cycle that modulates cellular proteostasis is translation. Changes in levels or mutations in the components of translational machinery have a significant impact on longevity in several animals. For instance, mutation or depletion of ribosomal proteins and translation factors extend lifespan in yeast worms and flies. Similarly, blocking the mTOR (mammalian Target of Rapamycin) system through rapamycin reduces protein synthesis and increases lifespan. While the significance of protein synthesis in the aging process is widely accepted, it is unclear whether errors in protein synthesis or translational fidelity may play a part in aging per se.

Protein synthesis error rates in bacterial systems are estimated to be as high as 1 in 10^3 per amino acid. According to this estimation, up to 15%-20% of the cellular protein pool may contain mistranslation errors. Mistranslated proteins may not have a significant impact on cellular proteostasis at a young age, due in part to the quick turnover and efficient clearance of cellular proteins. However, in the older animal, protein turnover rates, proteasome activity, and autophagy decline, making them more sensitive to error-prone protein translation. Therefore, mistakes in protein translation have the potential to cause a variety of age-related diseases. So far, however, it was unclear whether accurate translation can affect cellular aging and if the rate and extent of mistranslation increase with aging.

Researchers recently proposed a mechanism of aging that is highly dependent on translational accuracy. The authors study ribosomal protein RPS23, a homolog of prokaryotic S12 protein that is conserved in all three domains of life, and implicate it in the maintenance of protein translational accuracy. The ribosomal protein S12 (eukaryotic homolog RPS23) contributes to translation accuracy. A single amino acid alteration in a ribosomal protein present in archaea can improve metazoan translation fidelity and survival. The authors conducted a comprehensive phylogenetic analysis of RPS23 and discovered that a lysine residue at position 60 is evolutionarily conserved, except in hyperthermophilic archaea, where arginine replaces it (RPS23-K60R).

CRISPR gene editing was used to insert a mutation into the Drosophila melanogaster Rps23 gene, which led to the substitution of the lysine 60 with an arginine residue. The translational accuracy of mutant and wild-type flies was determined with a reporter construct that contained a renilla luciferase gene followed by a firefly luciferase gene separated by an in-frame linker sequence containing a stop codon. Inclusion of a stop codon produces firefly only if a read-through error had occurred, and thus served as a measure of translational accuracy. It was discovered that the K60R mutation in the RPS23 protein decreased the frequency of mistakes made during protein synthesis, thereby leading to a reduction in firefly luciferase production in the mutants. Specifically, the stop-codon read-through increased considerably with aging in the control flies, but not in the RPS23-K60R mutant. Similar results were obtained in Caenorhabditis elegans and Schizosaccharomyces pombe (yeast), where the expression of the RPS23-K60R protein also reduced stop-codon read-through.

Given that the variant (RPS23 K60R) was initially discovered in hyperthermophilic archaea, the authors contended that the protein should provide an evolutionarily conserved mechanism of heat tolerance. Indeed, flies, worms, and yeast expressing RPS23-K60R protein were able to grow and survive at temperatures above the optimum. Finally, the physiological benefit of this mutation was demonstrated by an increase in healthy lifespan. The authors demonstrate that when the mutation was introduced, it improved lifespan by 9%-23% in all three model organisms. Additionally, the authors extend their findings by noting that treatments that prolong lifespan (such as rapamycin) do so by enhancing translational fidelity in controls but not in mutant K60R strains. Thus, they concluded that the primary determinant of the aging process was a reduction in translational fidelity.

Researchers recently proposed a version 2.0 of the amyloid cascade hypothesis regarding the development of Alzheimer's disease. This was provoked by the failure of amyloid-clearing immunotherapies to produce meaningful benefits in patients. Those results require rethinking the role of amyloid-β in Alzheimer's disease. Some researchers theorize that amyloid-β aggregation is a side-effect of the real disease process, which is more a matter of persistent viral infection and consequent chronic inflammation in brain tissue. The amyloid hypothesis 2.0 keeps amyloid-β front and center as the primary early stage disease mechanism, however. The question is whether the right type or localization of amyloid-β is being targeted by current research programs: almost certainly not, given the poor results to date.

Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the original Amyloid Cascade Hypothesis (ACH). In ACH2.0, in contrast to ACH, Alzheimer's disease (AD) is driven by intraneuronal amyloid-β (iAβ) rather than extraneuronal amyloid-β and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived iAβ activates. Then upon reaching a critical threshold, the AβPP-independent iAβ-generating pathway triggers a devastating second stage resulting in neuronal death.

While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intracellular rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only iAβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD.

Whereas the notion of differentially derived iAβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived iAβ-activated self-sustaining mechanism producing a yet undefined deleterious "substance X" which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the iAβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD.

Link: https://doi.org/10.3233/ADR-220079

One of the noteworthy aspects of immune aging is a growing bias towards the creation of myeloid cells (such as monocytes) at the expense of the creation of lymphoid cells (such as the thymocytes that mature into T cells) in the bone marrow. This changes the overall behavior of the immune system for the worse. Researchers here find that the peptide angiotensin-(1-7) can be used to reverse some of these changes in mice, which is an interesting finding.

Aging is associated with chronic systemic inflammation largely due to increased myelopoiesis, which in turn increases risk for vascular disease. We have previously shown evidence for the therapeutic potential of Angiotensin-(1-7) (Ang-(1-7)) in reversing vasoreparative dysfunction in aging. This study tested the hypothesis that ischemic vascular repair in aging by Ang-(1-7) involves attenuation of myelopoietic potential in the bone marrow and decreased mobilization of inflammatory cells.

Young or Old male mice of age 3-4 and 22-24 months, respectively, received Ang-(1-7) for four weeks. Myelopoiesis was evaluated in the bone marrow (BM) cells by carrying out the colony forming unit (CFU-GM) assay followed by flow cytometry of monocyte-macrophages. Expression of pro-myelopoietic factors and alarmins in the hematopoietic progenitor-enriched BM cells was evaluated. Hindlimb ischemia (HLI) was induced by femoral ligation, and mobilization of monocytes into the blood stream was determined. Blood flow recovery was monitored and infiltration of inflammatory cells was evaluated by immunohistochemistry.

BM cells from Old mice generated a higher number of monocytes and M1 macrophages compared to that of Young, which was reversed by Ang-(1-7). Gene expression of selected myelopoietic factors, alarmins, and the receptor for alarmins, RAGE, was higher in the Old hematopoietic progenitor-enriched BM cells compared to the Young. Increased expressions of these factors were decreased by Ang-(1-7). Ischemia-induced mobilization of monocytes was higher in Old mice with decreased blood flow recovery and increased infiltration of monocyte-macrophages compared to the Young, all of which were reversed by Ang-(1-7). Enhanced ischemic vascular repair by Ang-(1-7) in aging is largely by decreasing the generation and recruitment of inflammatory monocyte-macrophages to the areas of ischemic injury. This is associated with decreased alarmin signaling in the BM-hematopoietic progenitor cells.

Link: https://doi.org/10.1038/s41598-023-29853-w

Much of the progress that takes place year after year in any segment of the broader biotech industry is invisible, and the growing portion of that industry focused on aging and longevity is no exception. Biotech is not a high profile industry, particularly because of the heavy dependence on intellectual property and trade secrets as a basis for government-granted monopolies on particular treatments. Details are kept quiet least larger entities in the industry to decide replicate a therapy and call it their own, because the potential rewards are worth the near certainty of a lawsuit. Thus every visible presentation or press release typically discusses only the very top of a near entirely buried edifice of hard work and research.

Today I'll point out a look back at the more visible news from 2022 in the industry, put together by one of the newer longevity-industry-focused venture funds, quadraScope. I help out by advising the fund principals, one of whom is an investor in the company I co-founded with Bill Cherman, Repair Biotechnologies. One example of the web of connections that ties the community together. The longevity industry and its investors is a growing but still comparative small community, and building networks of collaboration and connection is an essential part of that progress.

Longevity biotech progress in 2022

Despite the economic challenges of 2022, the emerging longevity biotech industry made impressive progress on several fronts, including positive results in clinical trials of senolytics and mitochondrial replacement therapies. Unity Biotechnology, backed by billionaires Jeff Bezos and Peter Thiel, reported positive results from a multicenter randomized clinical trial of a new senolytic drug to treat diabetic macular edema, a common cause of blindness in diabetic patients. Several companies, including Deciduous Therapeutics, Oisin Biotechnologies, and Cleara Biotech, are developing senolytic therapies to treat debilitating chronic conditions such as pulmonary fibrosis, diabetes, and cancer.

Mitochondrial replacement to restore cellular energy production is expected to be highly impactful for age reversal. Minovia, an Israeli biotech company, demonstrated the feasibility of transplanting mitochondria into humans. Although Minovia is treating an illness, their achievement suggests that a similar treatment could be used to enhance healthspan. In Minovia's clinical trial, children with single large-scale mitochondrial DNA deletion syndromes, a class of severe congenital mitochondrial diseases, received healthy mitochondria from their mothers. The benefits of the therapy were still evident one year after the transplant. Multiple startups are working on treatments to restore or replace aging mitochondria, including Mitrix Bio, Cellvie, Stealth BioTherapeutics, and Yuva Biosciences.

If proven feasible, cellular reprogramming could restore cell health and resilience, and treat diseases and disabilities caused by aging. 2021 and 2022 were the setup years for reprogramming with billions in funding and several ventures started. Ventures working on reprogramming include Altos Labs, NewLimit, Calico, Life Biosciences, Rejuvenate Bio, and Turn Biotechnologies. Altos Labs scientist Dr. Reik developed a method to reprogram cells, reversing their biological age by 30 years. Another Altos Labs scientist, Dr. Izpisua Belmonte, showed that long-term reprogramming was safe and could reverse age-related organ damage in mice. His group also developed an RNA-based therapy to reverse biological age and reduce inflammation in mice.

As a companion piece to a recent discussion of whether mild dehydration is both quite prevalent and meaningfully impacts aspects of aging, one might look at this study of water consumption and vascular health in hyperuremic individuals. A relationship between lower water intake and arterial stiffness was only significant in women, but nonetheless it is interesting to see data that suggests at least some populations are harming themselves over the long term via too little water intake.

Hyperuricemia is defined as an elevated serum uric acid (sUA) level in the blood and is well-known as an independent risk factor for the development of hypertension, metabolic syndrome, and cardiovascular disease. Water is essential to most bodily functions, and its consumption rates appear to decline with age. The aim was to evaluate the influence of water intake on early vascular aging in metabolic middle-aged patients with hyperuricemia.

The study included 241 men aged 40-55 years and 420 women aged 50-65 years from the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention program. Anthropometric characteristics, blood pressure, laboratory testing, and the specialized nutrition profile questionnaire were evaluated. Carotid-femoral pulse wave velocity (cfPWV), assessed using applanation tonometry, was evaluated as an early vascular aging parameter in patients with hyperuricemia and with normal sUA levels.

72.6% of men and 83.1% of women drink insufficient amounts of water (less than 1.5 L per day). However, our results showed statistically significant relationships only among a group of women. The women in the hyperuricemic group had a higher cfPWV than women with normal sUA levels. In hyperuricemic women, drinking less than 0.5 L per day in combination with other risk factors, such as age, increasing fasting glucose, and systolic blood pressure, was statistically significantly associated with an increased cfPWV.

Link: https://doi.org/10.3390/nu15030723

A number of mitochondrially derived peptides are thought to have positive effects on cell function, though as for most of the approaches of this nature, it is unclear that it is any better than a structured exercise program. One of the better studied of these peptides is MOTS-c, which is itself upregulated by exercise - arguably one of a number of known exercise mimetics. Delivering signal molecules that are normally upregulated by exercise should in principle recapture some of the beneficial effects of exercise, but so far this line of development has yet to much improve on exercise itself.

Mitochondria are organelles required for the production of ATP. A mitochondrion exhibits semi-autonomous genetic systems, independent genomes, and unique genetic codes that are similar to those found in bacteria. Recently, a short open reading frame (sORF) encoded in the mitochondrial genome has been discovered. These sORF produce bioactive peptides, collectively known as mitochondrial-derived peptides (MDP), which have a wide range of physiological functions and can explain how mitochondria communicate within and between cells in a specific disease environment. Mitochondrial-derived peptides may answer the key biological problems that have plagued the field for decades (such as mitochondrial-nuclear communication, metabolic dysfunction, etc.). Whether in the form of mitochondrial-derived peptide itself or in terms of sORF, mitochondrial-derived peptide is suitable for research as a therapeutic agent.

Mitochondrial-derived peptide called MOTS-c has been shown to significantly reduce the level of pro-inflammatory factors in mice and increase anti-inflammatory factors and insulin-stimulated glucose treatment rates, as well as glucose homeostasis. Furthermore, human studies showed that exercise increased MOTS-c levels in skeletal muscle and blood circulation, indicating that MOTS-c is a mitochondrial-derived peptide induced by skeletal muscle exercise. Additionally, studies have revealed the importance of MOTS-c in regulating obesity and diabetes, longevity, and cardiovascular disease. Specifically, this paper discusses the application of mitochondrial-derived peptides, including MOTS-c, in the treatment of diseases and anticipates the future development direction of MOTS-c combining synthetic biology to provide new ideas on how it can be developed and applied.

Link: https://doi.org/10.3389/fendo.2023.1120533

Senescent cells accumulate with age throughout the body, and cause considerable disruption to tissue structure and function via their pro-inflammatory secretions. Clearing senescent cells is an important approach to rejuvenation and reversal of age-related disease, based on the impressive results produced in mice to date. One of the challenges inherent in the destruction of senescent cells is the variation shown in their biochemistry, depending on how they become senescent and on which tissue they reside in. Different treatments exhibit widely varying outcomes for different varieties of senescent cell, and those varieties are far from fully or comprehensively catalogued.

In today's open access paper, researchers describe a novel approach to the selective destruction of senescent cells, focusing on characteristics of the dysfunctional iron metabolism exhibited by cells that become senescent in response to the signaling of other senescent cells, undergoing what is know as paracrine senescence. The researchers show that should be possible to produce an iron-activated prodrug, in which the active cell-killing drug substance is masked by a chemical addition that is only stripped in cells that exhibit the aberrant iron metabolism characteristic of senescent cells. It is worth noting that prodrugs based on the high levels of β-galactosidase in senescent cells have shown considerable promise to date, so we might expect analogous approaches to be similarly interesting.

Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis

The molecular biology of cellular senescence has opened the possibility of exploiting the differential vulnerabilities of senescent cells (SCs) compared with healthy cells for the development of a new class of longevity therapeutics against aging and age-related disorders. However, the significant heterogeneity among SCs based on cell type of origin or senescence induction method suggests the need to develop senolytics that either have a broader therapeutic efficacy or that can target recalcitrant SCs.

In this context, paracrine senescence (PS) is the least understood type of senescence. Even though there have been previous efforts to characterize PSs, the fact that only a subset of cells exposed to the senescence-associated secretory phenotype (SASP) factors become senescent means that previous experimental protocols were compromised, with mixed cell populations dominated by non-senescent cells labeled as PSs. We were able to circumvent this major methodological issue by isolating and enriching PSs using the previously characterized SC surface marker DPP4.

We discovered that DPP4+ paracrine SCs (PSDPP4+) engage prosurvival pathways that are distinct from those on which DPP4+ primary SCs (SDPP4+) rely and are also relatively resistant to killing by senolytic drugs previously identified to be effective against primary SCs. Given that SCs accumulate ferrous iron (Fe(II), also known as labile iron), we sought to test a Fe(II)-targeting strategy in which Fenton reaction of a prodrug was coupled to release of drug payload. Others previously showed that the tumor-activated prodrug TRX-CBI (comprising a trioxolane-based [TRX] sensor of Fe(II) conjugated to a cytotoxic cyclopropylbenzindoline [CBI] payload) demonstrated selective toxicity in Fe(II)-rich cancer cells.

Here, we used a form of TRX-CBI to target cytotoxic CBI to SCs. We demonstrated that treatment with TRX-CBI triggers significant senolysis of both PSDPP4+ and SDPP4+, with negligible cytotoxicity toward non-senescent cells. Based on our results, we propose Fe(II)-based targeting of SCs with ferroptosis inducers or iron-activated drug conjugates as broad-spectrum senolytic agents.

The primary approach to the prevention and treatment of mitochondrial aging undertaken by the SENS Research Foundation is allotopic expression, putting backup copies of mitochondrial genes into the nuclear genome. This prevents mitochondrial DNA mutations from degrading mitochondrial function in ways that can become pathological. This isn't the only approach on the table, however, and here some of the others are outlined.

Mitochondrial mutations - and above all, large deletions in the mitochondrial DNA - accumulate in long-lived cells over our lifetime. And until we can do something to repair or bypass that problem, the overtaking of this small fraction of our cells by deletion-bearing mitochondria will continue to drive diseases of aging. Long before there was a SENS Research Foundation - even before a "Strategies for Engineered Negligible Senescence" (SENS) platform existed - our founding CSO Dr. Aubrey de Grey surveyed the possible solutions for this problem, and the only one that seemed viable was allotopic expression (AE).

So why - after making great leaps forward with the science - are we now breaking ground on entirely new MitoSENS strategies? A few reasons. Considered at the most fundamental level, AE itself is an inherently difficult biotechnological challenge. Then there's the additional hurdle of delivering it to those cells that are vulnerable to mitochondrial mutations with age. Thus scientists in our MitoSENS lab are now working on two of these alternative strategies - both of them also thought up or endorsed by Dr. de Grey. You might think of them as backup strategies for the backup copies.

One of these strategies is to use a form of mitochondrial transplantation to replace the cell's mutation-bearing mitochondria with healthy ones. For mitochondrial transplantation to work as a rejuvenation biotechnology, we need a way not only to get the transplanted mitochondria into the cells, but to enable them to bypass the selective advantage of the native mitochondria, and especially of the powerful advantage of mutation-bearing mitochondria. This is where the relatively new biotechnology of "gene drives" come in. Engineered mitochondria would use restriction enzymes designed to target one of the several restriction sites that are naturally present in the host's mitochondria. The restriction enzyme would quickly go to work eviscerating the cell's original mitochondrial DNA, thereby clearing space to allow the new, transplanted mitochondria to take over.

We can't say much about the second strategy the MitoSENS team is exploring because it's a very early-stage project, and we want to be sure we're on the right track before making any announcements. All we'll say for now is that our scientists have identified a drug that may potentially "unmask" deletion-bearing mitochondria, attracting the attention of the mitophagy machinery and allowing it to cull them. Under some circumstances, such "unmasking" is sufficient to keep deletion-bearing mitochondria at bay when they haven't yet overtaken the cell. If the drug we're testing (or a similar one) could do that, we might be able to keep many cells operating normally by holding deletion-bearing mitochondria down to a minority of the population, and keep other cells free of deletion-bearing mitochondria entirely by catching the first one and sending it to its grave.

Link: https://www.sens.org/mitosens-new-strategies-gene-drive-mitophagy/

This article lists a variety of types of activity and project that might be undertaken to help to speed up the development of ways to treat aging as a medical condition. If you don't have a background in the life sciences, but nonetheless find human longevity a compelling topic, and would like to work in the field, what can you do? That is a good question, and often asked. There are many options that don't involve working as a scientist in a laboratory, though educating yourself about the science helps a great deal when it comes to picking the better options from the array of choices on the table.

Aging is a set of molecular and cellular processes that affects us all, but what if we could extend our healthy lifespan and live longer, healthier lives? This is the goal of the rapidly growing field of longevity. And after my last post about leaving my CTO job to work on longevity a lot of people have reached out asking what I'm working on actually? What I'm building for longevity? The short answer is... nothing. Yet. The long answer is... well, this post. I believe that anyone can work on anything they put their mind to if they are willing to put in the time and effort to learn the necessary skills. Whether it's research, funding, talent, media, practical longevity, aging therapeutics, or infrastructure, there are numerous opportunities to make a significant impact in this field.

$6.96 billion was raised across 96 funding rounds in 2022. This may seem like a lot but it's actually nothing. Remember that Instagram was acquired for $1 billion. So trying to bring more funding to the longevity field is very much needed. Someone needs to help talented people transition into the field. And believe me, we need far, far more people working on longevity. Recruiting and community building are important. The narrative around longevity is changing towards a more strategic conservatism which is proving to have better adoption. But it's far away from reaching a mainstream level. We need more communicators designing and evolving new narratives for different people.

The first drug targeted to extend healthy lifespan by 10-20 years could be developed and commercialized this decade. Aging therapeutics usually means getting the science out of the lab. So most often than not, someone with biology background will try to start or join a startup around their expertise. But what about people who are not coming from academia? The reality is that it may take anything from 6 months to 1 year (maybe even more) of full dedication to gain enough context, map the gaps, understand low hanging fruits, understand which technologies are the most promising, and get in love with a strong hypothesis to join or build a startup around it. This is the hardest part: in an ocean of possibilities, which one to choose? Which one is the most interesting? What technology is the most promising? What are the low hanging fruits?

Link: https://www.stanete.com/work-on-longevity/

Angiogenesis is the process of building new blood vessels in response to circumstances, such as a relative lack of oxygenation in tissues, or repair of injury. It is quite complicated, involving several distinct stages and the interactions of a variety of different cell populations. Angiogenesis declines with age, particularly in the context of maintaining capillaries. The density of capillary networks is reduced with age, and this may be quite influential in the aging of energy-hungry issues such as the brain and muscles. It isn't just a reduction in delivery of nutrients and oxygen. Loss of microvascular blood flow through tissues is likely also disruptive to the regulation of blood pressure, a factor contributing to the development of hypertension.

Which of the mechanisms of aging contribute to the loss of angiogenesis with age? Endothelial progenitor cells are one of the cell populations involved in angiogensis. In today's open access paper, the authors discuss cellular senescence in this population, and its negative effects on the capacity for angiogenesis, through the lens of microRNA regulation of these processes. Senescent cells grow in number with advancing age, in cell populations throughout the body. Their presence alters the cellular environment for the worse, generating inflammation and altered cell behavior. The research here provides just one example of many.

Hsa-miR-409-3p regulates endothelial progenitor senescence via PP2A-P38 and is a potential ageing marker in humans

Endothelial progenitor cells (EPCs), obtained from peripheral blood and identified as CD34 antigen-positive (CD34+) mononuclear cells, were marrow-derived stem cells and can differentiate into endothelial cells to promote neovascularisation in response to ischemic injury. Cell therapy using EPCs has been shown beneficial in ischaemia-related cardiovascular diseases (CVD) and emerged as useful substrates for neovascularization. However, some limitations make their clinical application difficult, such as heterogeneity in progenitor cell types, lack of standardization of specific surface markers and reduced number during ageing. Nonetheless, the angiogenic potential of EPCs has been an important target in regenerative medicine.

Numerous studies indicated that microRNA (miR or miRNA) is involved in post-transcriptional regulation of gene expression concerning diverse biological functions, including ageing and angiogenesis. A previous report showed that angiogenesis and tissue repair were regulated by miRNA-135a-3p via targeting p38 signalling in endothelial cells, revealing a link among miRNA, angiogenesis, and endothelial cells. In addition, increased miRNA-183-5p with age was involved in stem cell senescence. Furthermore, several studies have also addressed the regulation of miRNA during culture-induced senescence of vascular cells or in tissues.

These findings suggested that senescence and miRNAs may play an integrated role in modulating the pathologic processes of human CVD via the regulation of progenitor cell activity. We, therefore, in the present study explored the roles of hsa-microRNA (miR)-409-3p in senescence and signalling mechanism of human endothelial progenitor cells (EPCs). Hsa-miR-409-3p was found upregulated in senescent EPCs. Overexpression of miRNA mimics in young EPCs inhibited angiogenesis. In senescent EPCs, compared to young EPCs, protein phosphatase 2A (PP2A) was downregulated, with activation of p38/JNK by phosphorylation. Young EPCs treated with PP2A siRNA caused inhibited angiogenesis with activation of p38/JNK, similar to findings in senescent EPCs.

Inhibited angiogenesis of young EPCs after miRNA-409-3p mimics treatment was reversed by the p38 inhibitor. The effect of hsa-miR-409-3p on PP2A signalling was attenuated by exogenous VEGF. Analysis of human peripheral blood mononuclear cells (PBMCs) obtained from healthy people revealed hsa-miR-409-3p expression was higher in those older than 65 years, compared to those younger than 30 years, regardless of gender. In summary, hsa-miR-409-3p was upregulated in senescent EPCs and acted as a negative modulator of angiogenesis by regulating PP2A/p38 signalling.

In order to live longer, one needs to be more healthy, less impacted by dysfunction and damage, suffer fewer outright age-related diseases. This is what one sees when assessing centenarians against the average of the oldest populations. Aging is damage, and age-related disease is the manifestation of that damage. Different people age at different rates, largely the consequence of lifestyle choice and environmental factors such as exposure to persistent pathogens. It is also possible that genetic variants become more important in very late life by providing greater resilience, but so far the weight of evidence leans more towards lifestyle choice and luck when it comes to the small number of individuals who do survive to a century of age.

Centenarians exhibit extreme longevity and have been postulated, by some researchers, as a model for healthy aging. The identification of the characteristics of centenarians might be useful to understand the process of human aging. In this retrospective study, we took advantage of demographic, clinical, biological, and functional data of deceased individuals between 2014 and 2020 taken from the Basque Health Service electronic health records data lake. Fifty characteristics derived from demographic, clinical, pharmaceutical, biological, and functional data were studied in the descriptive analysis and compared through differences in means tests. Twenty-seven of them were used to build machine learning models in the predictive analysis and their relevance for classifying centenarians was assessed.

Most centenarians were women and lived in nursing homes. Importantly, they developed fewer diseases, took fewer drugs, and required fewer medical attendances. They also showed better biological profiles, exhibiting lower levels of glucose, hemoglobin, glycosylated hemoglobin, and triglycerides in blood analysis compared with non-centenarians. In addition, machine learning analyses revealed the main characteristics of the profiles associated with centenarians' status as being women, having fewer consultations, having fewer diagnoses of neoplasms, and having lower levels of hemoglobin.

Link: https://doi.org/10.3389/fpubh.2022.1096837

Researchers here discuss the proposal that Alzheimer's disease results from high sugar and glycemic carbohydrate intake. It is certainly possible that this mechanism contributes, but one has to ask why, if this was a dominant mechanism, is lifestyle much less correlated with Alzheimer's incidence than is the case for common metabolic diseases such as type 2 diabetes? One of the challenges all along with Alzheimer's is that it doesn't have a strong enough correlation with metabolic dysfunction and lifestyle choice to believe that it can be wholly, or even largely, a metabolic condition.

An important aspect of survival is to assure enough food, water, and oxygen. Here, we describe a recently discovered response that favors survival in times of scarcity, and it is initiated by either ingestion or production of fructose. Unlike glucose, which is a source for immediate energy needs, fructose metabolism results in an orchestrated response to encourage food and water intake, reduce resting metabolism, stimulate fat and glycogen accumulation, and induce insulin resistance as a means to reduce metabolism and preserve glucose supply for the brain. How this survival mechanism affects brain metabolism, which in a resting human amounts to 20% of the overall energy demand, is only beginning to be understood.

Here, we review and extend a previous hypothesis that this survival mechanism has a major role in the development of Alzheimer's disease and may account for many of the early features, including cerebral glucose hypometabolism, mitochondrial dysfunction, and neuroinflammation. We propose that the pathway can be engaged in multiple ways, including diets high in sugar, high glycemic carbohydrates, and salt. In summary, we propose that Alzheimer's disease may be the consequence of a maladaptation to an evolutionary-based survival pathway and what had served to enhance survival acutely becomes injurious when engaged for extensive periods. Although more studies are needed on the role of fructose metabolism and its metabolite, uric acid, in Alzheimer's disease, we suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine whether there is potential benefit in the prevention, management, or treatment of this disease.

Link: https://doi.org/10.1016/j.ajcnut.2023.01.002

Supercentenarians, much as one might expect, exhibit signs of being biologically younger than their years. It is a lower burden of age-related damage and dysfunction that allows them the chance to survive. That said, it is worth noting that many characteristics so far observed in studies of supercentenarians are also present in large numbers of people who die well before reaching a century of life. The fortunately biochemistry of supercentarians adjusts small odds of survival to be slightly more favorable, but still small odds of survival. It is far from an assurance, and it certainly doesn't prevent one from becoming frail and dependent. Supercentenarians are greatly impacted by aging, exhibiting a roughly 50% yearly mortality rate.

For these reasons, efforts to better understand the survival of supercentenarians seem to me to be a matter of scientific interest, but not a matter of practical interest. It is not the path that will lead to ways of ensuring meaningfully greater health and longevity for all. Today's open access paper is an example of this sort of research, a deeper dive into differences in epigenetic patterns exhibited in supercentenarians. Epigenetic decorations to DNA determine the expression of genes and thus behavior of cells. Given the advent of epigenetic clocks, measures of biological age based on characteristic age-related changes in specific sets of epigenetic marks on the genome, it is now possible to look at areas of the age-related portion of epigenetics, and declare that an individual's biochemistry appears either older or younger than the norm. Perhaps unexpectedly, supercentenarians are a mix of both.

Epigenetic profile of Japanese supercentenarians: a cross-sectional study

Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline.

Our findings show that the epigenetic ages of Japanese centenarians and supercentenarians were remarkably lower than their chronological ages, consistently with previous findings for Italian semi-supercentenarians, suggesting that their healthy longevity has an epigenetic basis. However, whether these epigenetic ages also reflect biological age has not yet been validated. Whether healthy longevity depends on slowing epigenetic ageing or on having a younger baseline DNA methylation state would be the next subject of interest. For our multiple-sampled centenarians and supercentenarians, the longitudinal changes in epigenetic age showed that their epigenetic ageing was slower than that indirectly inferred from the cross-sectional non-centenarian cohort. Further research comparing the longitudinal epigenetic change of centenarians and supercentenarians with non-centenarians will help to answer this question.

Our study further suggests a link between the specific epigenetic states and exceptional healthy longevity in centenarians and supercentenarians. Some epigenetic signatures in centenarians and supercentenarians were maintained at young states, whereas others were maintained at advanced (or old) states. Young-state DNA-methylation signatures were overrepresented around cancer-related and neuropsychiatric disease-related genes. Conversely, CpG sites with accelerated (advanced) demethylation were also detected in centenarians and supercentenarians. Knowledge-based analyses indicated that some of these demethylated CpG sites can affect the activity of TGF-β, a major anti-inflammatory cytokine. Given that many age-related diseases can develop as a consequence of excessive pro-inflammatory responses, anti-inflammatory responses, such as those mediated by TGF-β and other cytokines, are crucial for healthy ageing and longevity. For instance, immunoassays have identified greater TGF-β activity in centenarians than in younger controls.

Autophagy is the name given to a collection of maintenance processes responsible for clearing waste and damaged proteins and structures from the cell. Autophagy is implicated in aging. It is thought to become dysfunctional and less efficient in cells in aging tissues. Further, evidence suggests that improved autophagy is an important mechanisms in the slowing of aging produced by calorie restriction and a range of other interventions tested in laboratory species. Here, researchers discuss the relationship between aging and autophagy specifically in the context of Parkinson's disease and the role of inflammatory microglia in the progression of that condition. One might compare this with a very similar paper noted last week.

In a healthy organism, the homeostasis of the central nervous system (CNS) is dependent on the interactions of various nerve cells. However, in the CNS of Parkinson's disease (PD) patients, there is an aberrant build-up of α-synuclein (α-Syn) and a cascade effect of gradual neuronal damage that breaks the appropriate balance, which leads to inflammation in the CNS. Autophagy is an evolutionarily conserved degradation pathway that is responsible for the digestion and recycling of the majority of intracytoplasmic proteins and organelles. Autophagy maintains homeostasis by delivering cytoplasmic materials to the lysosome for degradation. Due to poor autophagy, inappropriately aggregated α-Syn in the CNS of PD patients cannot be removed and accumulated. Overall, dysregulation of autophagy is thought to play an important role in the abnormal aggregation of α-Syn and the exacerbation of Parkinson's disease.

Microglia are CNS-specific immune cells that play an immunological role in the CNS comparable to that of macrophages, interact with neurons, and conduct a variety of tasks in the CNS. Recent research shows that microglial autophagy is involved in the function and regulation of inflammation in the CNS. These findings implied that dysregulation of autophagy in microglia may impact innate immune activities, including phagocytosis and inflammation, which, in turn, contribute to illnesses associated with neuroinflammation. To date, many researchers have considered PD to be a neuroinflammatory disease, and the role of microglial autophagy in the pathophysiology of PD has been a hot issue in the field. In this review, we present and highlight the contribution of microglial autophagy to the pathological mechanism of PD and aimed to determine whether microglial autophagy could be a potential target for therapeutic intervention.

Link: https://doi.org/10.3389/fnagi.2022.1039780

Researchers here review the evidence for exercise to slow the onset and progression of neurodegenerative conditions. A mountain of evidence demonstrates exercise (and the practice of calorie restriction) to improve long term health and at least modestly slow age-related degeneration. For the cost, meaning essentially free, it is a good deal. The future will bring medical technologies that can greatly improve upon the benefits of exercise by targeting the underlying causes of aging, but for now it remains one of the best options on the table.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise has a positive impact on the life quality of elderly with neurodegenerative diseases. Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics. We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism.

Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.

Link: https://doi.org/10.3390/ijms24021175

The practice of calorie restriction extends life notably in short-lived mammals, but not in long-lived mammals, despite the short-term benefits to health appearing quite similar in mice and humans. This may be because many of the beneficial shifts in metabolism triggered by a low calorie intake are already built in to long-lived species, as a part of the history of evolutionary change that led to those species becoming long-lived. Since calorie restriction alters near every aspect of cellular biochemistry, coming up with a comprehensive understanding of the important mechanisms has been a slow process, never mind how those differences might then generate the large variation in effects on life span across species.

In today's open access paper, researchers apply epigenetic clocks to samples from a noted human study of calorie restriction that was conducted a while back. The clocks show little to no effect on biological age, but do suggest improvement in health that is on a par with the better lifestyle choices, such as choosing not to smoke or avoiding obesity. In the short term calorie restriction does indeed produce significant improvement in a range of markers of health related to inflammation, cardiovascular risk, and so forth. It is interesting that the presently favored epigenetic clocks are largely insensitive to this intervention.

Calorie restriction slows pace of aging in healthy adults

The CALERIE Phase-2 randomized controlled trial, funded by the US National Institute on Aging, is the first ever investigation of the effects of long-term calorie restriction in healthy, non-obese humans. The trial randomized 220 healthy men and women at three sites in the US to a 25 percent calorie-restriction or normal diet for two years. To measure biological aging in CALERIE Trial participants, the team analyzed blood samples collected from trial participants at pre-intervention baseline and after 12- and 24-months of follow-up. The team analyzed methylation marks on DNA extracted from white blood cells. DNA methylation marks are chemical tags on the DNA sequence that regulate the expression of genes and are known to change with aging.

In the primary analysis researchers focused on three measurements of the DNA methylation data, sometimes known as epigenetic clocks. The first two, the PhenoAge and GrimAge clocks, estimate biological age. The third measure studied by the researchers was DunedinPACE, which estimates the pace of aging, or the rate of biological deterioration over time. "In contrast to the results for DunedinPace, there were no effects of intervention on other epigenetic clocks. The difference in results suggests that dynamic 'pace of aging' measures like DunedinPACE may be more sensitive to the effects of intervention than measures of static biological age." The intervention effect on DunedinPACE represented a 2-3 percent slowing in the pace of aging, which in other studies translates to a 10-15 percent reduction in mortality risk, an effect similar to a smoking cessation intervention.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm), and is established to increase healthy lifespan in multiple species. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 years.

We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies, and contrasting with reports that biological aging may not be modifiable. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality.

Many more life span studies are carried out in mice rather than rats, so it is not too surprising to see people pushing the record for longest lived rat. The longest lived mice are those in which growth hormone receptor signaling is inhibited, while the longest lived rats are the result of life-long calorie restriction. The group noted here is pursuing a strategy of processing the blood plasma from young animals and then introducing the processed plasma into old animals. A treatment starting in mid-life produced a modest gain in median life span in rats, while the one still surviving rat from the small study group has surpassed the existing record for calorie restricted mice. It is an interesting data point for the field of dilution of blood plasma to reduce harmful factors present in the bloodstream of old individuals, though as I understand it, this group favors explanations involving factors from the processed young plasma that are beneficial.

Scientists working on an experimental anti-ageing therapy claim to have broken a record by extending the lifespan of a lab rat called Sima. Named after the Hindi word for "limit" or "boundary", Sima is the last remaining survivor from a group of rodents that received infusions of blood plasma taken from young animals to see if the treatment prolonged their lives. Sima, who was born on 28 February 2019, has lived for 47 months, surpassing the 45.5 months believed to be the oldest age recorded in scientific literature for a female Sprague-Dawley rat, the researchers say. So far, Sima has outlived her closest rival in the study by nearly six months.

Researchers have rushed to produce and trial therapies based on young blood plasma after numerous experiments found that infusions could reinvigorate ageing organs and tissues. The results from the latest study will be written up when Sima dies, but data gathered so far suggests that eight rats that received placebo infusions of saline lived for 34 to 38 months, while eight that received a purified and concentrated form of blood plasma, called E5, lived for 38 to 47 months. They also had improved grip strength. Rats normally live for two to three years, though a contender for the oldest ever is a brown rat that survived on a restricted calorie diet for 4.6 years.

Results from such small studies are tentative at best, but some scientists believe the work, and similar efforts by others, has potential. A preliminary study found that infusions of young blood plasma wound back the biological clock on rat liver, blood, heart and a brain region called the hypothalamus. A patent filing on the potential therapy describes how plasma from young mammals is purified and concentrated before use. Some components, such as platelets, are removed, as they can trigger immune reactions.

Link: https://www.theguardian.com/science/2023/feb/08/anti-ageing-scientists-extend-lifespan-of-oldest-living-lab-rat

Researchers here report on the results of disabling the MLKL gene involved in necroptosis, a form of programmed cell death. This reduces age-related inflammation in female mice, and delays loss of lymphocyte production in male mice. The changes are not enough to produce differences in apparent signs of aging, such as mortality rate, however. The scientific challenge here lies in linking reduced necroptosis to the observed changes in immune aging, as is usually the case in any change that is broadly related cell survival or fundamental cell activities such as replication. This sort of activity can keep research teams busy for years, but it is unclear as to whether there is a practical outcome at the end of the tunnel given that the mice didn't fare any better for the change.

MLKL is one of the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here, we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl-/- mice on a congenic C57BL/6J genetic background.

Our extensive histopathological and immunophenotypic cohort analyses have identified several unique, sex-specific, differences between congenic C57BL/6J Mlkl-/- mice and their wild-type littermates that emerge with age. Several statistically significant findings were observed in hematological parameters across age in Mlkl-/- mice compared to wild-type littermate controls. Many of these parameters remained within normal range despite statistical significance, suggesting they are unlikely to assert biologically critical roles.

Of note, Mlkl-/- mice exhibit increased circulating lymphocyte numbers relative to wild-type littermates at 12-14 months of age. A comprehensive and unbiased blind scoring of inflammatory foci in more than 44 different sites revealed a 62% decrease in background, sterile inflammation of the skeletal muscle, bone, cartilage, adipose tissue, and connective tissue proper in 17-month-old female Mlkl-/- relative to age-matched wild-type littermates. It is important to consider, however, that these differences in age-related circulating lymphocyte numbers and tissue inflammation did not manifest in any overt differences in the general condition, mobility, or mortality of these mice up to 17 months of age.

Link: https://doi.org/10.1038/s41418-023-01121-4

The evidence of recent years from studies of calorie restriction and intermittent fasting might lead one to suspect that the length of time spent being hungry is an important determining factor, on a par with calorie intake. In the course of physiological hunger, a range of signaling processes kick in and cell behavior changes in response. Is this important in distinction to the lower level nutrient sensing processes inside cells? So much changes in the course of fasting or calorie restriction that it is challenging to pick out the most relevant mechanisms.

One of the noteworthy mechanisms of hunger is ghrelin signaling. In this study, researchers stimulate the ghrelin receptor using a suitable small molecule for much of the lifespan of mice, and observe the results. The overall extension of life span is a quarter of that produced by calorie restriction, and so we might draw some conclusions from that as to the relative importance of hunger in the benefits resulting from the practice of calorie restriction or fasting. Interestingly, the short term weight gains observed in mice given this ghrelin receptor agonist in the past don't appear in this long term study, in which the controls are the heaver animals. This is possibly because the researchers didn't allow the mice to overeat, by pairing their consumption with that of the untreated control animals.

The effect of a pharmaceutical ghrelin agonist on lifespan in C57BL/6J male mice: A controlled experiment

Of the well-studied effects on lifespan in mouse models, detailed mechanisms underlying the health and longevity benefit of caloric restriction (CR) are still being investigated despite some limitations on the practical applications to humans. A major limitation of animal models is that they cannot self-report hunger or other physiological sensations that would inform mechanistic work. Since ghrelin was first described and noted as a growth hormone secretagogue receptor (GHS-R) agonist, much study has focused on the effects on hunger and appetite regulation along with other aspects of energy balance.

Investigators examining effects on cognition in mouse models have posited that the mechanism may involve interoceptive cues or signaling, rather than reduced energy intake per se. In those studies, oral administration of a ghrelin agonist (LY444711, an orally active compound that binds with high affinity to and is a potent activator of the growth hormone secretagogue receptor 1a [GHS-R1a] receptor, reduces Alzheimer's disease pathology and improves cognition in the APP-SwDI mouse model. Treatment also reduced levels of amyloid beta (Aβ) and neuroinflammation (as measured by microglial activation) at 6 months of age compared to controls, like the effect seen in the 20% CR group (gp) but with no significant difference in body weight (BW) or percentage body fat.

LY444711 binds to the human ghrelin receptor (GHS-R1a) and is a functional agonist. This agonist produced orexigenic behavior in rodents, including stimulated energy intake (food consumption is 40% than controls at 10 mg/kg and 50% greater than controls at 30 mg/kg dose), positive energy balance (23% greater BW with 2 weeks treatment at 10 mg/kg), acute higher respiratory quotient (RQ) with increased dose, and increased adiposity (greater fat mass but no significant difference in lean mass). The authors conclude this substance is orally active with an extended half-life relative to native ghrelin.

Despite various studies on ghrelin effects on food intake and body composition, studies of ghrelin agonists on lifespan-extending effects in rodent models are lacking. We tested the hypothesis that a pathway related to perceived hunger, as induced by an oral, exogenously administered orexigenic agent (i.e., a synthetic ghrelin agonist), would affect lifespan in mice. Mice aged 4 weeks were allowed to acclimate for 2 weeks prior to being assigned (N = 60/group). Prior to lights off daily, animals were fed LY444711 or a placebo control until death. Treatment (GhrAg) animals were pair-fed daily based on the group mean food intake consumed by controls (ad libitum feeding) the prior week. Results indicate an increased lifespan effect for GhrAg versus controls, which weighed significantly more than GhrAg (adjusted for baseline weight). Further studies are needed to determine the full scope of effects of this ghrelin agonist, either directly via increased ghrelin receptor signaling or indirectly via other hypothalamic, systemic, or tissue-specific mechanisms.

Microglia are innate immune cells of the central nervous system. Microglia in the aging brain respond to the age-damaged environment by becoming more activated, inflammatory, and ultimately senescent. They amplify the inflammatory environment, contributing further to damage and loss of function. One approach is to clear these cells, readily achieved using available CSF1R inhibitor drugs, after which a new population emerges that, for a time at last, is not overly activated and inflammatory. Here, researchers discuss a different approach to reducing microglial activation, without clearing the entire population of microglia, in the context of age-related blood-brain barrier dysfunction.

While it's well established that chronic mild hypoxia promotes a robust angiogenic response, we recently found that it also triggers transient blood-brain barrier (BBB) disruption, that is associated with aggregation and activation of microglia around the leaky blood vessels. Importantly, microglial depletion markedly enhanced vascular leak, demonstrating an important vasculo-protective function for microglia in maintaining BBB integrity. As a high integrity BBB is a critical determinant of cerebral health, yet evidence suggests that BBB integrity declines with age, we recently examined how aging influences both the extent of hypoxia-induced BBB disruption and the associated vasculo-protective function of microglia. This showed that compared to young (8-10 weeks) mice, the number of hypoxia-induced vascular leaks was greatly amplified (5-10 fold) in aged (20 months) mice in all regions of the brain examined.

When we analysed the impact of aging on microglia activity, we discovered an interesting paradox. On the one hand, microglia in aged brain were far more activated as assessed by morphological criteria and expression of activation markers such as Mac-1 and CD68, but on the other hand, they displayed a marked deficit in the ability to aggregate around leaky blood vessels. These findings are consistent with the work of others who showed microglia in aged brain are typically more activated than in young mice. Interestingly, microglia in the aged brain can be re-programmed by removing all microglia with the colony stimulating factor-1 receptor (CSF-1R) antagonist PLX5622, and then allowing the central nervous system to repopulate with new microglia displaying a younger phenotype. Notably, this approach was shown to reverse age-related cognitive decline, although vascular integrity was not examined.

In our study we took the simpler approach of reducing microglial activation state in the aged brain by treating mice with minocycline and this successfully reduced the number of hypoxia-induced vascular leaks. Based on these data, we proposed a biphasic relationship between microglial activation and vasculo-protection, such that microglia need to become activated to confer protection, but if they become too activated, as in the aged brain, this protection declines.

Link: https://doi.org/10.18632/aging.204509

The accumulation of senescent cells with age is an important contributing cause of age-related disease and eventual mortality. These errant cells secrete a potent mix of pro-growth, pro-inflammatory signals that disrupt normal tissue maintenance and change cell behavior for the worse, leading to structural changes and loss of organ function throughout the body. Damping senescent cell signaling, such as by selectively destroying senescent cells, has shown considerable promise as a basis for rejuvenation therapies, and the sooner that the existing approaches are widely adopted for use by the elderly population, the better.

An increase in life expectancy in developed countries has led to an insurgency of chronic aging-related diseases. In the last few decades, several studies provided evidence of the prominent role of cellular senescence in many of these pathologies. Key traits of senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secretory phenotype (SASP) resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senescence is a highly phenotypically heterogeneous process, hindering the discovery of totally specific and accurate biomarkers.

Strategies to prevent the pathological effect of senescent cell accumulation during aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies and some are already in early stages of clinical translation. The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiological functions. In this review, we explore the heterogeneous phenotype of senescent cells and its influence on the expression of biomarkers currently used for senescence detection. We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies.

Link: https://doi.org/10.1124/pharmrev.122.000622

Minicircle is working towards the upregulation of follistatin, an inhibitor of myostatin and thus an interesting target for improved muscle growth and treatment of sarcopenia. Follistatin and myostatin are well studied genes in this context, and there are any number of animal studies, as well as human trials of various approaches to myostatin inhibition. As I have long said, follistatin and myostatin are probably the most compelling, least risky genes to start working on if interested in gene therapy development. There is a great deal of animal and human data to support this work.

It is always annoying to see shabbily written popular science articles in which ignorance is brandished with a sort of pride. The author of today's article couldn't get Minicircle to comment on the details of their work, has no real idea as to what is going on under the hood, and so forges ahead with a mix of snark and commentary from various people who also don't know what Minicircle is doing, or the nature of their gene therapy approach.

I am a participant in the Minicircle follistatin trial. I've also signed a non-disclosure agreement, so don't ask me for details. The company has an interesting, novel technology for the delivery of gene therapies, and is undertaking a responsible, low-cost, first-in-human clinical trial outside the US with educated volunteer participants from the self-experimentation community. It consistently amazes me, the degree to which hostility is poured upon those who choose not to engage with the journalistic and regulatory priesthoods in exactly the approved fashion.

The present system of regulation, and the enormous costs it imposes on development and discovery, must change. We live in an era in which a prototype gene therapy can be safely assembled for a few thousand dollars in cost of goods. It cannot continue to be the case that development only progresses at a cost of tens of millions of dollars to reach initial human trials, and hundreds of millions to billions of dollars to allow the average person to be permitted to use a treatment.

This biohacking company is using a crypto city to test controversial gene therapies

Over the past few years, a parade of newly released gene therapies have consecutively claimed the title of most expensive drug in the world; the current honor goes to the $3.5 million hemophilia B treatment Hemgenix, launched in November 2022. Minicircle is taking something of a different tack. The startup, which is registered in Delaware, aims to fuse elements of the traditional drug testing path with the ethos of "biohackers" - medical mavericks who proudly dabble in self-experimentation and have long hailed the promise of DIY gene therapies. 

The eccentricities don't end there. Minicircle's trials are going ahead in Próspera, an aspiring libertarian paradise born from controversial legislation that has allowed international businesses to carve off bits of Honduras and establish their own micronations. It's a radical experiment that is allowing a private company to take on the role of the state. While much attention has been paid to the charter city's use of Bitcoin as legal tender, the partnership with Minicircle is an important milestone toward another goal - becoming a hotbed of medical innovation and a future hub of medical tourism.

It's against this unusual backdrop that Minicircle is trying to lead biohacking's charge into the mainstream, or at least somewhere near it-studying gene therapies that target familiar conditions like muscular disorders, HIV, low testosterone, and obesity, and doing so with the backing of tech moguls and under the purview of bespoke "innovation-friendly" regulation. It ultimately aims to democratize access to gene therapies, with an emphasis on discovering the right nucleic cocktail to promote longevity. 

Most scientists I spoke with are less than enthusiastic about Minicircle's undertaking, expressing skepticism about its methods and aims, while experts in medical ethics are concerned about how the trials will move forward - and what they could mean for the burgeoning and sometimes unscrupulous medical tourism industry.  These experts also say the red-tape-trimming stance of special economic zones like Próspera can set off alarm bells (though the charter city staunchly defends its regulations).

At least one prominent scientist sees a potential upside to growth in the biohacking space: George Church, a professor of genetics at Harvard Medical School who has previously consulted on biohacking endeavors, tells me he welcomes the evolution of biohacking self-experimentation into full-blown clinical trials. He isn't familiar with Minicircle's work specifically, but he says of the general premise, "As long as nothing goes wrong, it could herald a revolution in cost reduction." That, of course, is a big caveat. 

Neurogenesis is the process by which new neurons are produced from neural stem cells and then integrated into existing neural circuits in the brain. Adult neurogenesis is important to memory function, as well as to the resilience of the brain to injury and degeneration. Neurogenesis declines with age, and is noted to be one of the many aspects of neural biology that is negatively impacted by the onset of Alzheimer's disease. Is this loss of neurogenesis secondary to the better known disease mechanisms associated with Alzheimer's? Is it important enough to be pursued as a basis for therapy? Researchers here discuss the topic.

The hippocampus, a critical hub for cognition and memory, is one of the first brain regions to be affected in Alzheimer's disease (AD) patients. The dentate gyrus (DG), a hippocampal subfield implicated in learning and memory, particularly in pattern separation, shows substantial age-related functional decline in humans, non-human primates, and rodents. The DG is further unique as it contains the so-called "neurogenic niche," wherein stem cells continue to generate new neurons in the adult brain, in a special form of cellular plasticity referred to as "adult hippocampal neurogenesis" (AHN). Adult-born dentate granule cells (aDGCs) functionally incorporate into the granule cell layer of the DG as part of the hippocampal circuitry, where they, via their unique physiological properties, play key roles in neural plasticity and cognition. AHN has been shown to be impacted by (several aspects of) AD pathology in both rodents and humans.

Despite a substantial focus on amyloid and tau pathologies over the past decades, disease-modifying therapies for AD are still lacking. Hence, "mapping" the full mechanistic heterogeneity of AD, i.e. beyond amyloid and tau, is an important critical step to developing novel therapeutic targets. Key mechanistic questions as to what renders an individual vulnerable or resilient to developing AD remain unanswered, but may be "hidden" in the brains of a unique group of elderly individuals with preserved cognition, despite the presence of substantial AD pathology. This "cognitive reserve" that is apparent in these subjects may likely increase resilience toward developing dementia. Notably, AHN levels in postmortem brains were recently correlated with ante-mortem cognition in mild cognitive impaired (MCI) and AD patients, pointing toward a potential active role of AHN in the buildup of cognitive reserve, which can later on confer resilience to AD-related dementia.

Here, we critically discuss current knowledge on the putative role of AHN in AD pathophysiology and resilience, focusing primarily on the human brain. We emphasize the importance of the multicellular complexity of the neurogenic niche where AHN resides, and hence the relevance of integrating both intrinsic and extrinsic signals from distinct cellular populations, into any future therapeutic strategies aimed to "rejuvenate" the AD brain.

Link: https://doi.org/10.1016/j.stem.2023.01.002

Senescent cells are created constantly throughout life, largely the result of somatic cells reaching the Hayflick limit on cellular replication. In youth, these cells are rapidly removed by the immune system, but this clearance falters in later life for reasons yet to be fully explored. Nonetheless, enough is understood to propose a variety of avenues by which the immune clearance of senescent cells can be improved.

Cellular senescence is a complex process involving a close-to-irreversible arrest of the cell cycle, the acquisition of the senescence-associated secretory phenotype (SASP), as well as profound changes in the expression of cell surface proteins that determine the recognition of senescent cells by innate and cognate immune effectors including macrophages, NK, NKT, and T cells. It is important to note that senescence can occur in a transient fashion to improve the homeostatic response of tissues to stress. Moreover, both the excessive generation and the insufficient elimination of senescent cells may contribute to pathological aging.

Attempts are being made to identify the mechanisms through which senescent cell avoid their destruction by immune effectors. Such mechanisms involve the cell surface expression of immunosuppressive molecules including PD-L1 and PD-L2 to ligate PD-1 on T cells, as well as tolerogenic MHC class-I variants. In addition, senescent cells can secrete factors that attract immunosuppressive and pro-inflammatory cells into the microenvironment. Each of these immune evasion mechanism offers a target for therapeutic intervention, e.g., by blocking the interaction between PD-1 and PD-L1 or PD-L2, upregulating immunogenic MHC class-I molecules and eliminating immunosuppressive cell types.

In addition, senescent cells differ in their antigenic makeup and immunopeptidome from their normal counterparts, hence offering the opportunity to stimulate immune response against senescence-associated antigens. Ideally, immunological anti-senescence strategies should succeed in selectively eliminating pathogenic senescent cells but spare homeostatic senescence.

Link: https://doi.org/10.1016/j.bj.2023.02.001

It is time once again for my once-yearly set of unsolicited thoughts on biotech startups that I'd like to see join those already working hard on the basis for human rejuvenation. The industry is growing rapidly, but patchily. Partial reprogramming has received enormous attention, as has the development of senolytics. Meanwhile, other important goals in rejuvenation research languish, or presently have only one or two companies involved in clinical translation of promising academic projects. Many plausible paths forward go undeveloped; there are just as many opportunities to make a real difference in the world as there were a decade ago.

Cell Therapy for Thymus Regrowth

The thymus atrophies with age, reducing the production of new T cells to a fraction of what it once was. The adaptive immune system declines as a result, becoming cluttered with dysfunctional, broken, and worn cells. One of the more promising approaches to regrowing the aged, atrophied thymus involves intravenous delivery of cells, either progenitor thymocytes or endothelial cells, that home to the thymus. Once there, they promote growth of active thymic tissue. This has been demonstrated in mice, but the groups involved have moved on to try to find small molecule approaches, so far with only very limited progress to show for it. So why not take this cell therapy approach and bring it to the clinic? Production of universal cells from lines engineered to avoid immune rejection is presently a going concern. This is a good time to be innovating in the cell therapy sphere.

Bring Fecal Microbiota Transplantation into Widespread Use

One particular implementation of fecal microbiota transplantation was recently approved by the FDA for use in the treatment of C. difficile infection. Beyond this formal arena of medicine, there is a thriving community of individuals attempting to treat their own dysbiosis, and informal clearing houses that attempt to characterize and screen donor samples for safer use. It is well demonstrated in animal models that fecal microbiota transplantation from young to old produces a lasting rejuvenation of the gut microbiome, improved health, reduced inflammation, and extended life span. The timing has never been better to establish a venture that demonstrates the merits of this approach in humans, and then does its best to make fecal microbiota transplants available to the millions of older people who could benefit.

A Better Approach to Reversing Tissue Calcification

The state of the art in reversal of the calcium deposition and consequence loss of elasticity in the aged cardiovascular system and elsewhere is typified by Elastrin's technology, which is to say a focus on ways to improve on the established mode of EDTA chelation therapy by using a far more targeted delivery system. Is there a better way forward that can lead to larger effect sizes, a greater reduction in calcification? One would think that there should be, indeed must be if this aspect of aging is to be fully reversed.

Solutions to the Systemic Delivery Issues of Gene Therapy

Presently available gene therapy delivery techniques struggle to achieve a number of important goals. Delivery to the liver may be more or less a solved problem, but many other problems remain unsolved. Sufficient delivery throughout the body without excessive delivery to the lungs or liver following intravenous injection, for example. Or delivery to a specific minor internal organ, with minimal delivery elsewhere, following intravenous injection. Delivery platforms that can provide relatively off the shelf, 80/20 solutions to delivery of gene therapy payloads in these and other important circumstances have yet to be brought into being, but are very much needed.

A Way to Inhibit Alternative Lengthening of Telomeres

Targeting telomerase and telomeres in the clinical treatment of cancer has started in earnest with Maia Biotechnology. It remains the case that something like ~10% of cancers use alternative lengthening of telomeres (ALT) rather than telomerase to bypass limits on cell replication, however, and there is as of yet no good approach to inhibition of ALT. One of the reasons why ALT is an attractive target is that it does not operate in normal, non-cancerous cells, which removes many of the normal issues regarding off-target effects in the inhibition of cellular mechanisms. There is room here for a group to perform a broad screen for ALT inhibitor small molecules, in search of a useful lead for a preclinical development program.

Safely Replace the Hematopoietic System

The generation of immune cells occurs in the bone marrow, the responsibility of hematopoietic stem cells and descendant progenitor cell populations. While the mechanisms of aging, particularly chronic inflammation, are disruptive of the niche structures that support hematopoietic cells, there is also damage to the cells themselves. It has long been possible to replace hematopoietic cells, but this is a procedure that requires aggressive chemotherapy to clear existing populations, and comes with a non-trivial degree of risk. To introduce a new population of engineered hematopoietic stem cells into most old people, an entirely new, safer, and more gentle strategy will be needed. Consider the production of universal or patient-matched hematopoietic stem cells that are changed in ways that allows them to outcompete native cells and take over stem cell pools in the bone marrow, for example.

SIRT3 beneficially affects mitochondrial function, and its upregulation is a calorie restriction mimetic strategy, since it mediates some of the benefits resulting from a lowered calorie intake. Given this, there is some interest in this as a basis for treatments for neurodegenerative conditions, in which loss of mitochondrial function in the brain is thought to be an important contribution to pathology. Mitochondria are the power plants of the cell, and the brain requires a great deal of energy to operate. So far, efforts to improve mitochondrial function in aged tissues by targeting the expressed levels of specific proteins or metabolites important to mitochondrial metabolism have yet to surpass the effects of exercise or the practice of calorie restriction itself. It seems unlikely that manipulating SIRT3 expression will prove to be any different.

SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3's functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key role in brain energy metabolism and provides substrate flexibility to neurons. It also facilitates metabolic coupling between fuel substrate-producing tissues and fuel-consuming tissues. SIRT3 mediates the health benefits of lifestyle-based modifications such as calorie restriction and exercise.

SIRT3 deficiency is associated with metabolic syndrome (MetS), a precondition for diseases including obesity, diabetes, and cardiovascular disease. Alzheimer's disease (AD) has been reported to coexist with these diseases in aging populations. SIRT3 downregulation leads to mitochondrial dysfunction, neuroinflammation, and inflammation, potentially triggering factors of AD pathogenesis. Recent studies have also suggested that SIRT3 may act through multiple pathways to reduce plaque formation in the AD brain. In this review, we give an overview of SIRT3's roles in brain physiology and pathology and discuss several activators of SIRT3 that can be considered potential therapeutic agents for the treatment of dementia.

Link: https://doi.org/10.3390/ijms24021615

Finding ways to inhibit the formation of toxic amyloid-β oligomers in the aging brain may prove to be a useful treatment for Alzheimer's disease, but it remains the case that therapies targeting amyloid-β have yet to show meaningful patient benefits. It is possible that the wrong type or location of amyloid-β was targeted, or that amyloid-β is not directly responsible for Alzheimer's disease, but rather a side-effect of other disease processes. Regardless, a great deal of effort still goes into targeting aspects of amyloid-β biochemistry, in the hopes that one of these approaches will succeed where past efforts have failed.

Because plaques are visible under a microscope, scientists long believed that they are responsible for damaging neurons in Alzheimer's disease etiology. Many clinical trials took place and billions in funding were invested over more than a quarter of a century to generate molecules and antibodies targeting and preventing formation of fibrils and plaques. Such treatments proved unsuccessful and caused intolerable side effects. Over time, fibrils and plaques themselves were deemed non-toxic, and instead earlier soluble intermediates known as oligomers are now considered the culprits in this insidious disease.

Recent clinical trials using antibodies to target oligomers have shown promising results. Researchers are now developing small cyclic peptides that have proven effective in animal models in treating the disease by targeting oligomers. When these molecules were combined in a test tube with the small protein amyloid beta, the generation of oligomers was completely blocked, and no subsequent aggregation occurred. In the next stage, the researchers incubated human neurons with the toxic oligomers and the cyclic peptides. Most neurons remained alive, but those in the control group that were exposed to the oligomers without cyclic peptides were severely damaged and died.

Next, transgenic mouse models of Alzheimer's disease in the pre-symptomatic stage were treated with the cyclic peptides and observed over time for memory functions and amount of amyloid beta oligomers in the brain. Through molecular imaging, the researchers determined that the mice didn't generate substantial amounts of oligomers and, consequently, didn't develop any sign of Alzheimer's.

Link: https://www.eurekalert.org/news-releases/978766

Changes in the function and activity of microglia in the brain, innate immune cells analogous to the macrophages present in the rest of the body, are known to be involved in the onset and progression of neurodegenerative conditions. Aging and neurodegeneration are associated with a growing presence of both senescent microglia and activated microglia Both of these states producing inflammatory signaling, contributing to the chronic, unresolved inflammation of brain tissue that is also characteristic of later life.

Autophagy is the name given to a collection of cellular maintenance processes responsible for recycling damaged and unwanted proteins and structures within the cell. Autophagy is thought to decline in effectiveness with age, and this leads to a growing garbage catastrophe in cells, particularly in long-lived cells. Here, researchers discuss the connection between failing autophagy in immune cells such as microglia and trigger mechanisms such as the inflammasome that are responsible for a sizable fraction of inflammatory signaling. It may be that inflammation will prove to be the central pillar of neurodegeneration, but that inflammation has numerous contributing causes.

Microglial autophagy in Alzheimer's disease and Parkinson's disease

Autophagy and its dysfunction are associated with a variety of human pathologies, including aging, neurodegenerative disease, heart disease, cancer, and metabolic diseases, such as diabetes. A plenty of drugs and natural products have been found to modulate autophagy function through multiple signaling pathways. Small molecules or nanomedicine that can regulate autophagy seem to have great potential to intervene in neurodegenerative diseases that are largely due to the accumulation of misfolded proteins.

In general, microglia participate in autophagy by phagocytosis in the central nervous system (CNS). Because of the critical role of autophagy in protein and organelle quality control, the impairment of autophagy will result in accumulation of aggregated proteins and damaged organelles, which are common pathological hallmarks in AD and PD. Accumulating evidence indicates that the autophagy machinery in microglia can contribute to the emergence, acceleration, or amelioration of CNS disease conditions. So far, two specific mechanisms appear to be relevant to CNS pathology: activation of the inflammasome and increase of autophagy protein-mediated endocytosis/phagocytosis. Autophagy pathways are implicated in the regulation of inflammasome function at various steps by removing triggering agents, inflammasome constituents, or downstream effector molecules. As the major cellular component of the innate immune system in the brain, microglia have been found to execute pivotal functions during CNS homeostasis and pathology.

Microglial autophagy and inflammatory response are necessary for protecting against external stimuli. When the inflammatory response in the brain is continuously activated, overactivated inflammasomes can cause neuronal damage. As early as 2006, it was reported that neuronal autophagy dysfunction induces neurodegenerative diseases in mice, and recent studies have linked microglial autophagy to NLR family pyrin domain 3 (NLRP3) inflammasomes, elucidating the important role of NLRP3 inflammasomes activation triggered by autophagy deficiency in microglial cells in the development of Parkinson's disease (PD).

NLRP3, a widely studied oligomeric multiprotein inflammasome complex, is highly expressed in microglia. Microglial hyperactivation of the NLRP3 inflammasome has been well-documented in various neurodegenerative diseases, including PD. Autophagy protects the nervous system by clearing NLRP3 inflammasome activation. Likewise, inflammasome signaling pathways can also regulate microglia activation necessary to balance between required host defense inflammatory response and to prevent excessive and detrimental inflammation.

Study data here shows that age-related enlargement of perivascular spaces in the brain is to some degree driven by raised blood pressure, and reversible given control of blood pressure. As the researchers note, this enlargement is a part of the issues that lead to a reduced clearance of metabolic waste from the brain in later life. This reduced clearance is likely an important factor in the development of neurodegenerative conditions. All told, the raised blood pressure of hypertension is one of the more important ways in which deeper causes of aging are converted to tissue dysfunction and outright structural damage throughout the body. Even without addressing the underlying causes, forcing a reduction in blood pressure via antihypertensive drugs reduces mortality and risk of a range of age-related conditions.

Among people who received more intensive treatment for high blood pressure, evaluations of MRI scans indicated a positive change in brain structures involved in its ability to clear toxins and other byproducts. The study is the first to examine whether intensive blood pressure treatment may slow, or reverse structural changes related to the volume of the brain's perivascular spaces, areas of the brain around the blood vessels that are involved in the clearance of toxins and other byproducts. These areas tend to enlarge as people get older or have more cardiovascular risk factors.

"If the brain cannot properly clear toxins and metabolic byproducts, they will accumulate and may contribute to the development of dementia. Some research has proposed that the pulsations of the cerebral arteries with each heartbeat help to drive the clearance of these toxic brain byproducts in the perivascular spaces. However, high blood pressure over the long term stiffens arteries, impairing function and the ability to clear toxins, resulting in enlargement of perivascular spaces."

The researchers analyzed brain MRI scans for 658 participants (average age of 67 years, 60% women) of the SPRINT-MIND MRI substudy. After an average 3.9-year follow-up period, 243 people in the intensive treatment group (systolic blood pressure goal of 120 mm Hg) and 199 people in the standard treatment arm (systolic blood pressure goal of 140 mm Hg) had pre- and post-MRI scans that were analyzed for the percentage of brain tissue taken up by perivascular spaces.

In MRI scans taken when the study began, the percentage of brain tissue occupied by perivascular spaces was higher among the patients who were older and had a greater volume of white matter hyperintensities. After controlling for age and sex of the participants, at the start of the study, the volume of perivascular spaces was similar among participants in both blood pressure treatment groups. After almost 4 years of high blood pressure treatment, the volume of perivascular spaces had decreased significantly in the intensive treatment group but did not change in the standard treatment group.

Link: https://newsroom.heart.org/news/ideal-blood-pressure-may-remodel-brain-clearance-pathways-linked-to-brain-health-dementia

A range of evidence suggests that persistent viral infection contributes to the risk of suffering neurodegenerative conditions such as Alzheimer's disease. This may be due to mechanisms relating to amyloid-β accumulation, in its role as an anti-microbial peptide, a part of the innate immune system. It may have more to do with lasting chronic inflammation subsequent to infection. Researchers here note another addition to the epidemiological data on this topic, in this case linking severe infections requiring hospitalization with later dementia risk. The effect sizes here are large and last for a long time following infection, but one might wonder how much of this relates to the degree of age-related immune dysfunction and other impacts of aging that lead from infection to hospitalization versus being able to work through it with clinical visits and over the counter medication only.

Previous research suggested infection with HSV increases a person's risk of developing Alzheimer's disease (AD). Likewise, someone who caught Epstein-Barr virus (EBV), which causes mononucleosis, is a whopping 32-fold more likely to develop multiple sclerosis (MS). Now, researchers have analyzed medical records from 344,000 people from the Finnish nationwide biobank, FinnGen, and 106,000 in the U.K. Biobank. All participants were of European ancestry and older than 60 at baseline. About 405,500 were healthy, while 44,500 had been diagnosed with an NDD: 11,650 with AD, 2,750 with vascular dementia, 18,700 with all-cause dementia, 7,200 with Parkinson's disease, 840 with amyotrophic lateral sclerosis, and 3,500 with multiple sclerosis.

Researchers compared NDD diagnosis to prior hospitalization with 32 common viral illnesses, including flu, pneumonia, viral warts, chickenpox/shingles, viral encephalitis, and meningitis. Viral exposure was based on hospital billing codes, so the researchers could not say whether it was the infection or something else that sent a person to the hospital. Any one of 12 of the illnesses correlated with a higher incidence of any of the six NDDs in both databanks. Notably, most of these viral illnesses are caused by neurotropic viruses - those that are able to get into the central nervous system (CNS) and into neurons. These include influenza viruses, HSV, the herpes zoster virus that causes chickenpox/shingles, various enteroviruses that cause meningitis, and EBV.

Which viral illness posed the greatest NDD risk? People who had had viral encephalitis were 31 times more likely to develop AD and 40 times likelier to have dementia of any kind than were people not hospitalized for infection. Likewise, AD risk jumped a whopping 62-fold after meningitis. And it was not just infections of the brain. People hospitalized for a viral intestinal infection had three to five times the risk of developing AD or vascular dementia. Viral hepatitis tripled PD risk, while herpes zoster boosted the likelihood of developing vascular dementia and MS two- to sixfold.

Since infections are typically acute and neurodegenerative disease can advance slowly over years or decades, researchers wondered if the risk for NDDs wanes after infection. They found that it was highest the first year, then fell over 15 years. For example, hazard ratios for all-cause dementia slid from 83 within a year of viral encephalitis to 24 over the next four years, then to five by year 15. What does this all mean for middle-aged folks? Researchers noted that all these cases were in people who had severe symptoms and, therefore, didn't represent someone who rode out the flu or shingles at home. Preventing severe viral illness by getting vaccinated against the flu, pneumonia, or shingles may partially protect someone from getting an NDD. Indeed, a previous analysis concluded that people who got flu or pneumonia shots were less likely to get AD than the unvaccinated.

Link: https://www.alzforum.org/news/research-news/nothing-sneeze-viruses-raise-risk-neurodegenerative-disease

Inflammatory signaling is made up of a broad range of different molecules, some of which are better studied than others. Chronic, unresolved inflammation increases with age and is disruptive to tissue structure and function. The research community spends more time investigating ways to interfere in this signaling (such as the TNF inhibitors used to treat autoimmune conditions) than it does in search of ways to prevent chronic inflammation from occurring in the first place (such as senolytic therapies to remove senescent cells and their pro-inflammatory secretions). This is unfortunate, as suppression of specific inflammatory signals affects both excess, unwanted inflammation and necessary, useful inflammation. The result may be a net improvement, considering the alternative of no treatment, but it is certainly the case that immune function is degraded in ways that negatively affect long-term health.

The aging of the immune system into a state of chronic inflammation is a feedback loop in which inflammation produces further disruption of immune function by affecting processes and organs involved in the creation of immune cells. Atrophy of the thymus is accelerated by chronic inflammation, and so is the decline and altered function of hematopoietic stem cell populations in the bone marrow. Hematopoietic cell populations reside in niche structures, and these niches suffer as chronic inflammation ramps up with age. In today's open access paper, researchers quantify the contribution of one specific inflammatory signal molecule to this aspect of aging, and demonstrate that inhibition helps to slow down the loss of function.

Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing

Chronic inflammation is a hallmark of ageing, but its consequences for tissue function remain unclear. Here we demonstrated that bone marrow ageing is defined by niche remodelling, increased IL-1β production by dysfunctional stromal cells and activation of inflammatory response programmes in both haematopoietic and niche cells. This chronic, low-grade inflammation directly contributes to the loss of endosteal mesenchymal populations, impaired osteogenesis and vascular dysfunction. These changes, alongside expanded inflammatory LepR+ MSC cells, drive lineage biases and regenerative defects from the old blood system. Niche inflammation also activates emergency myelopoiesis pathways in hematopoietic cells, reinforcing myeloid cell production at the expense of lymphoid and erythroid commitment. This blunts regenerative responses that rely on acute activation of these pathways, which then cause exacerbated phenotypes following stress in old mice.

A reduction in endosteal niches and expansion of neurovascular central marrow niches that promote megakaryopoiesis through increased production of pro-inflammatory cytokines, including IL-6 and IL-1β, has been previously described. In addition, a role for IL-1β produced by aged macrophages has been implicated in promoting megakaryopoiesis, and for IL-1β produced by myeloid cells in response to the ageing microbiome in promoting myelopoiesis. Here we showed that chronic IL-1β production by endosteal stromal cells acts in trans to induce inflammatory remodelling of marrow LepR+ MSC cells and contributes to many aspects of altered blood production with age, in particular chronic engagement of emergency myelopoiesis. Conversely, blocking IL-1 signalling attenuates central marrow LepR+ MSC niche inflammation and dampens hematopoietic stem cell activation, recovering some differentiation biases and improving acute regenerative potential. We also found that blocking TNFα, another candidate mediator of these effects, did not prevent niche or blood ageing, which highlights the central role of IL-1.

Our findings add to the growing body of evidence for microenvironmental inflammation in driving blood ageing and the specific importance of IL-1β as a driver of this process. They establish IL-1 as a central factor that damages the crosstalk between the bone marrow niche and the blood system, with inflammatory remodelling of the central marrow probably having deleterious consequences for innervation and vascular function. Consistently, IL-1β levels correlated with age-related mortality in human studies. They indicate a potential application of IL-1 inhibitors to improve blood production in the elderly, especially in regenerative settings following chemotherapy or immunosuppression.

The practice of calorie restriction slows aging, albeit to a much greater degree in short-lived mammals than is the case in our own species. Evidence suggests that upregulation of the cellular maintenance processes of autophagy are the primary mechanism by which calorie restriction produces its benefits to health and life span. Calorie restriction produces a major reshaping of all aspects of cellular behavior, however, a wide range of epigenetic changes that, along with autophagy, are the subject of the discussion in this open access paper.

Autophagy, such as a double-edged sword, can maintain cell survival and delay aging, but excessive autophagy can lead to cell death and promote aging. Therefore, how to precisely regulate and activate autophagy while clarifying the interaction between autophagy and epigenetic modifications may contribute to the proposal of anti-aging methods. Epigenetic modification, unlike DNA mutations, is a reversible regulation. CR prevents aging and aging-related diseases, in part through autophagy and reversing abnormal aging-related epigenetic alterations. This suggests that epigenetic modification is expected to be a potential therapeutic strategy against aging and its aging-related diseases. Further understanding of the role of epigenetics in human aging and longevity requires a deeper understanding of the influence of the external environment on epigenetics, such as the mechanism of epigenetics in CR-mediated longevity regulation.

Observational studies have shown that CR also has beneficial effects on human longevity. Among many well-known anti-aging strategies, CR has been identified as one of the effective interventions to combat the aging process and age-related pathological diseases (e.g., diabetes, kidney disease, cardiovascular disease, cancer, Alzheimer's disease, etc.). Thus, CR may influence the aging process by favorably affecting human health, and it is of considerable importance to be used to identify the underlying signaling mechanisms of aging. Mechanisms that extend lifespan through CR modulation of autophagic function or epigenetic modifications have also gradually been explored and focused. In this paper, we focus on autophagy and epigenetics to explore the molecular mechanism of caloric restriction delaying aging and its interactive relationship, providing a basis for the study of aging.

Link: https://doi.org/10.3389/fcell.2022.1079920

Some higher species, such as salamanders and zebrafish, are capable of complete regeneration of damage to organs as adults, including central nervous system tissue such as the retina. In mammals, with a very few limited exceptions, this type of regeneration is only possible during embryonic development. Is it possible to enable adult mammals to regenerate like zebrafish through some adjustment to the regulation of genes? That is the reason why researchers are attempting to understand the cellular differences that enable proficient regeneration. In recent years, attention has focused on the interaction of macrophages and senescent cells during wound healing, suggesting that something in their behavior is important for regeneration.

Zebrafish spontaneously regenerate their retina in response to damage through the action of Müller glia. Even though Müller glia (MG) are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration with precise temporal roles for macrophages and microglia.

Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging, but are still metabolically active, releasing pro-inflammatory signaling molecules as part of the Senescence Associated Secretory Phenotype (SASP). Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia/macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after damage.

Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.

Link: https://doi.org/10.1101/2023.01.16.524296

If interested in the evolution of aging, today's open access paper opens with a very readable tour of the history of thought on this topic, as well as the more recent debate between different classes of hypotheses that seek to explain the evolution of aging. The authors are opinionated, and the path leads to their favored theory, involving population-wide effects driven by infectious disease that do not require group selection, but it nonetheless covers a lot of ground and makes for an educational read. Theories of aging are much debated, perhaps in part because there are so many exceptions to the rule that must be explained away. The long lives and negligible senescence of naked mole-rats, the apparent physical immortality of hydra, the large variance in life span between near neighbor species in similar ecological niches, and so forth.

As things stand, the mainstream position on the evolution of aging is that it results from natural selection operating more strongly on early life features than on later life features. Systems and mechanisms are selected for their ability to improve early reproductive success, regardless of whether or not they fall apart later in life. Aging is inevitable, but only a side-effect of the dominance of early reproductive success as a strategy. Alternatively, and as the authors note, it is possible that aging provides some sort of benefit in evolutionary competition, and is thus under direct selection. The range of possible benefits are subtle and may only take effect over very long periods of time, however, making it hard to mount a compelling argument based on evidence rather than modeling. This is a field unlikely to come to complete consensus in the near future.

Is Aging an Inevitable Characteristic of Organic Life or an Evolutionary Adaptation?

A group of adaptive hypotheses claims that aging evolved to control epidemics of infectious diseases. Indeed, pathogens are a universal and powerful selective factor, and the intrinsic disease-independent mortality (lifespan setpoint) of the host is an important parameter in epidemiological models. If the probability of an individual becoming infected is equivalent across the lifespan and no recovery is presumed, older individuals are expected to be infected more often than younger ones. So, the removal of older individuals by aging obviously results in a decrease in chronic pathogen load. If one assumes that infection adversely affects reproduction, shortening the lifespan might paradoxically result in an increase in the population growth rate.

Disease-mediated selection of a shorter lifespan was also suggested as a hybrid model involving elements of population density control, acceleration of evolution, and disease prevention with the emphasis on overcrowding as a reason for epidemic. However, neither model is a universal explanation of aging. Both involve group selection, a condition believed to be rare in nature. Both require constant severe epidemics to sustain the selective pressure against the longer lifespan, a premise that contradicts observations. Furthermore, such epidemics should promote a fast selection of host resistance.

Using realistic epidemiological and population dynamics models, we constructed a theoretical framework, supporting the idea that pathogens may be the force behind the evolutionary benefit of aging. The new model proposes that aging can be a unifying adaptation to limit the establishment and progression of infectious diseases. First, we found that populations of short-lived individuals, in addition to reduced pathogen prevalence, bestow additional benefits when facing epidemics. Novel pathogens infecting a new host species from another species or the environment might require substantial time to adapt to a new host. Our model shows that the shorter lifespan of a species might limit the time window available for such chronic pathogens to evolve better transmissibility, thus preventing zoonotic transmissions.

Next, we found that dramatic declines in infected population densities - bottlenecks - during natural oscillations or migration into a new environment might be associated with pathogen clearance. If the last infected founders die before the density is reconstituted to levels permissive for epidemics, the pathogen will become extinct in that population. This effect depends directly on the species' lifespan. Thus, a short lifespan has population-level benefits. A simulation designed based on this hypothesis demonstrated the scenario of short lifespan selection.

Regarding the pathogen properties, the model assumes chronic pathogens with strong negative effects on reproductive fitness. Such pathogens are present in nature: evolutionary parasitology predicts pathogens to rather sterilize their hosts than shorten their lifespan to facilitate transmission. We found that pathogens with too high or too low infectivity cannot mediate selection of shorter lifespan: if a pathogen is transmitted at a very high level, it infects short-lived and long-lived populations both at high levels, producing no selectivity. If transmission is too low, the prevalence of the pathogen and, therefore, its adverse effects on long-lived strain population growth is insufficient. Selection favoring short lifespans requires a highly (90%) sterilizing pathogen or a combination of mildly (10-40%) sterilizing diseases that can provide a strong cumulative penalty in coinfected hosts.

We modeled a population of short-lived individuals invaded by a long-lived mutant. With this model, we observed the stabilizing selection of shorter lifespans that occurred by the following mechanism: (i) in the early stages, the pathogens and long-lived mutants are spatially separated from each other, allowing mutants to expand due to their low mortality, (ii) the pathogens spread in the area occupied by long-lived hosts and, due to the reasons described above, becomes more prevalent than in short-lived hosts, (iii) higher pathogen prevalence results in higher sterilization and lineage-specific population decline that, in combination with population pressure of short-lived populations, results in a complete displacement of the long-lived individuals.

Unlike previous models of pathogen control type, our scenario does not require group selection or ongoing severe epidemics to explain a limited lifespan setpoint. Importantly, our hypothesis also mitigates the problems associated with the evolution of the host's resistance to pathogens: selective pressure towards the shorter lifespan might be provided by zoonotic pathogens, the exposure to these pathogens is limited, and the likelihood for the evolution of resistance is reduced. In another scenario involving several milder pathogens, each of these pathogens confers only a little selective power to drive the evolution of resistance.

Sepsis isn't an age-related condition per se, but it is more likely and more dangerous when it occurs in older people. A sizable part of that is thought to arise from the aging of the immune system and its predisposition to chronic inflammation. Researchers here argue that age-related changes in the gut microbiome also conspire to increase the severity of sepsis when it occurs. Gut microbiome aging is likely also connected to the aging of the immune system, as it fails to remove problem microbes as efficiently as it does in youth. There are other contributing factors, however, including lifestyle choices such as diet and exercise.

In the most simplistic terms, sepsis is a severe host-pathogen interaction. However, sepsis definitions (and research investigations) are largely focused on the host response to the pathogen, as opposed to the pathogen itself. Within this framework, the pathogen is often seen as a static, homogeneous infectious insult that triggers the dysregulated host response. Accordingly, exaggerated sepsis severity outcomes in the aging population have been attributed to either an age-associated waning of immune function (i.e., immunosenescence), or an alteration in baseline inflammatory response (i.e., inflammaging). However, therapeutics targeting the host immune response or inflammatory cascade have consistently failed to improve clinical outcomes of septic patients, in any age group. Conversely, therapeutic strategies targeting the pathogen with antimicrobial agents have consistently demonstrated significant decreases in sepsis-associated morbidity and mortality.

Given the importance of the pathogen to sepsis outcomes, we sought to determine if longevity-associated changes in gut microbial virulence contribute to aging-associated sepsis severity. We hypothesized that throughout the lifetime of the host, the gut microbiota accumulate virulence factors that promote host immune evasion. Escape of these age-conditioned pathogens from the intestinal lumen therefore leads to exaggerated sepsis severity. This novel concept - that the gut microbiota also "ages" throughout the lifespan of the host and selects for hypervirulent pathobionts - has the potential to inform targeted therapeutic approaches to mitigate the burden of sepsis in older adults.

We utilized two complementary models of gut microbiota-induced experimental sepsis to establish the aged gut microbiome as a key pathophysiologic driver of heightened disease severity. Our findings highlight a previously unrecognized contributor to the pathophysiology of heightened aging-associated sepsis severity. To date, investigations of the intersection of aging and critical illness have focused on longevity-associated host processes such as waning immune function and alterations in inflammation. However, it is intuitive that the intestinal microbiota simultaneously undergoes genomic and phenotypic changes throughout the lifespan of the host organism. This aging of an enteric bacterial community likely selects for pathobionts with virulence factors that offer a fitness benefit - such as the evasion of host immunity. Our work highlights that pathogen virulence factor genomics, and not simply type of pathogen, is therefore a major mediator of mechanistic sepsis heterogeneity.

Link: https://doi.org/10.1101/2023.01.10.523523

Why does increased klotho expression extend life in mammals? While evidence shows klotho to improve cognitive function, it is also thought to largely function in the kidneys, and thus effects on brain aging are indirect. The research noted here challenges that, though it is conducted on cells in culture, not in living animals. The researchers suggest that klotho will reduce age-related inflammation in brain tissue by suppressing the inflammatory response of glial cells. Reduced inflammation will in turn slow brain aging and loss of cognitive function. Whether this in vitro behavior will hold up in vivo remains to be established; there continues to be some debate as to whether klotho is meaningfully active in the brain in the context of aging.

Glia are non-neuronal cells of the brain and nervous system. There are several subtypes of glial cells, including astrocytes, oligodendrocytes, and microglia. A new study involved in vitro experiments using a lipopolysaccharide (LPS) to induce inflammation in cultured glial cells. Lipopolysaccharides are components of Gram-negative bacteria cell walls that can cause an acute inflammatory response by triggering the release of pro-inflammatory cytokines in various cell types, potentially leading to cell death.

The researchers set out to see whether pre-treatment with klotho could protect glial cells against the surge in levels of pro-inflammatory mediators after the administration of LPS. The results showed for the first time in cultured neural cells that klotho can indeed have anti-inflammatory and neuroprotective effects. Klotho not only acts on the metabolic coupling between neurons and astrocytes but is also an important player in modulating glia neuroinflammation. 

Link: https://agencia.fapesp.br/protein-with-anti-aging-action-combats-inflammation-and-avoids-death-of-neurons/40586/

Today's open access paper is a very readable tour of the present state of research and development of therapies targeting senescent cells, whether to destroy them or alter their function in favorable ways. In both cases the primary goal is to reduce the senescence-associated secretory phenotype (SASP), the pro-growth, pro-inflammatory signaling that contributes to degenerative aging as the number of senescent cells rises over the course of later life. It is hoped that clearance of senescent cells will produce a sizable positive impact for late life health, reducing chronic inflammation, slowing the onset of near all age-related conditions, and even reversing existing pathology. The animal studies are impressive when it comes to that last point.

Senescent cells are a good example of antagonistic pleiotropy. The transient presence of senescent cells and SASP is selected for because it is useful during embryonic development, and continues to provide benefits in early life, such as assisting in wound healing, and reducing cancer incidence. When senescent cells cannot be cleared efficiently in later life, and they linger, then they become harmful. Natural selection tends to produce situations of this nature, as selection pressure is strongest in early reproductive live span. It allows for the generation of systems and mechanisms that fall apart over time or otherwise become pathological in an aged body.

Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging

To date, a handful of senolytics have been examined in a variety of preclinical models. In naturally aged mice and atherosclerosis mouse models, the dasatinib and quercetin ("D + Q") administration improved cardiac function. In radiation-damaged mice, "D + Q" enhanced exercise capacity. In osteoporosis mouse models, administration of "D + Q" increased bone mass and strength, providing a novel treatment strategy for not only osteoporosis but multiple age-related comorbidities. Adipose tissue inflammation and dysfunction are causative for obesity-related diabetes and insulin resistance, but "D + Q" alleviated metabolic and adipose tissue dysfunction in obese mice, suggesting the potential of senolytics in treating obesity-related metabolic dysfunction and complications.

Senolytic agents have exhibited substantial efficacy in delaying, preventing or alleviating physical frailty, multiple cancers, and a variety of cardiovascular, liver, kidney, musculoskeletal, lung, eye, hematological, metabolic, and neuropsychiatric pathologies as well as complications of cancer treatment and organ transplantation. Through targeting fundamental aging mechanisms, which are considered as "root cause" contributors to multiple chronic disorders, senolytics hold the potential to alleviate over 40 or even more age-related conditions as illustrated by preclinical studies, thus opening a new avenue for treatment of age-related dysfunction and chronic pathologies.

So far, mounting lines of evidence support the efficacy of senescence-targeting agents, namely senotherapeutics, which mainly comprise senomorphics and senolytics. Early preclinical data about senolytics, small molecule agents that eradicate senescent cells, have shown promising indications of effectiveness across several aging and disease models. The first wave of in-human trials with the senolytic combination of "D + Q" suggested decreased senescent cell burden in adipose tissue of patients with diabetic kidney disease and improved physical function in patients with idiopathic pulmonary fibrosis (IPF). Clinical trials with other senolytics, including the flavonoid fisetin and Bcl-xL inhibitors, are currently in progress.

The first clinical trial of senolytics demonstrated improved physical function in IPF patients after "D + Q" administration in a first-in-human, open-label, and pilot study, warranting evaluation of "D + Q" in expanded randomized controlled trials for senescence-related disorders. Similarly, another pilot clinical trial reported that treatment with "D + Q" reduces senescent cell burden in adipose tissues of patients developing diabetic kidney disease. Specifically, adipose tissue activated macrophages and adipose tissue fibrosis were decreased, as were levels of circulating SASP factors, including IL-1α, IL-6, and matrix metalloproteinases (MMPs), confirming target engagement (senescent cell decreases) using a "hit-and-run" treatment strategy with senolytics.

More recently, an open-label early phase 1 trial of "D + Q" for Alzheimer's disease (SToMP-AD) reported that intermittent senolytic administration decreases tau protein accumulation and neuro-inflammation, preserves neuronal and synaptic density, partly restores cerebral blood flow and reduces ventricular enlargement. The results support the initiation of a randomized, double-blind and placebo-controlled multicenter phase II trial, which aims to further explore the safety, feasibility, and efficacy of senolytics in treating Alzheimer's disease.

The gut microbiome changes with age, the balance of microbial populations shifting to cause more inflammation and a lesser production of beneficial metabolites. To what degree can forms of fasting and time restricted feeding improve the aged gut microbiome? The authors of this paper seem optimistic, but more data is needed. Particularly, I'd want to see data in calorie restricted or intermittently fasted old rodents in direct comparison with the effects of fecal microbiota transplant from young animals. Obtaining human data for the same interventions should not be too challenging a prospect; it just requires the will and funding to run a small and informal clinical trial.

The manipulation of the gut microbiota composition through dietary changes and intermittent fasting (IF) has emerged as a potentially effective "pharmaco-nutritional" strategy for reversing dysbiosis and host metabolic disorders. However, the conventional medical care system does not yet have the capability of evaluating both the qualitative and quantitative changes that occur in the gut microbiota. At the population level, one potential strategy for the prevention and management of metabolic syndrome should involve the development of a set of approaches related to changes in the microbiota of the gut. TRF stands for time-restricted feeding in animals and time-restricted eating (TRE) in humans throughout a counted number of hours. It allows for a daily fasting duration that is greater than 12 hours, and it does so without affecting either the quality or quantity of the nutrients consumed. Through the involvement of circadian genes and the gut microbiome, time-restricted feeding/eating (TRF/E) provides protection against nutritional challenges that can lead to obesity and metabolic risks. It has been hypothesized that TRF/E may regulate and modulate gut microbiota in order to prevent metabolic disease through multiple pathways.

It is still too soon to determine how TRF/E affects the composition of the gut and the functions it performs through daily feeding and fasting rhythms. Previously, TRF imposed significant alteration in the microbial composition of human gut microbiota. There were substantial alterations and relative richness of bacterial communities in healthy persons using combined effect size measures from linear discriminant analysis (LDA). These communities were classified as either TRF or non-TRF. At the level of the genus, 34 bacteria were enriched in the TRF group, and 18 bacteria were enriched in the non-TRF group. The most numerous genera in the TRF group were Bacteroidetes and Prevotellaceae (prevotella 9 and prevotella 2), while the most numerous genera in the non-TRF group were Escherichia, Shigella, and Peptostreptococcus. Similarly, a study revealed that timed-feeding protocols (TRF, alternate day fasting and caloric restriction) induced measurable shifts in the bacterial compositions in mice that coincide with improvements in metabolism. TRF, on the other hand, was successful in reestablishing cyclical variation in several bacterial families that are thought to play a role in metabolism.

Link: https://doi.org/10.3390/nu15020259

Every cell contains hundreds of mitochondria, generating chemical energy store molecules to power cellular biochemistry. Mitochondrial function declines with age, with evidence indicating that a disruption of quality control mechanisms such as mitophagy is the proximate cause. Underlying that are age-related changes in the expression of proteins involved in mitochondrial dynamics, the fusion and fission of mitochondria. Is it possible to significantly improve mitochondrial function by forcing an upregulation of quality control mechanisms? Approaches such as delivery of NAD+ precursors have yet to reliably improve on the effects of exercise on mitochondrial function, but perhaps more is possible.

The disruption of mitochondrial function is usually caused by the excessive production of reactive oxygen species (ROS), the uncoupling of the mitochondrial electron transport chain (mtETC), or the expression of aberrant or mutated proteins encoded by mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). In addition, mtDNA is more susceptible to mutations due to its proximity to the site of ROS generation and the absence of histone protection. These perturbations are implicated in primary mitochondrial diseases, which are characterized by mutations that affect the nDNA or mtDNA, as well as various age-related diseases, metabolic disorders, heart pathologies, and cancer, which are referred to as secondary mitochondrial diseases.

Mitochondrial homeostasis and proteostasis are essential for the maintenance of mitochondrial function. To this end, mitochondria have renewal mechanisms, such as mitophagy or mitochondrial unfolded protein response (mtUPR), in addition to mitochondrial biogenesis that promotes the growth and formation of new mitochondria. Moreover, other renewal mechanisms have recently emerged, such as mitochondrial-derived vesicles (MDVs). The ability of mitochondria to release their contents into vesicles is a conserved process shared with their bacterial ancestors. When mitochondrial stressors are present, mitochondrial inner and outer membranes become oxidized, leading to their loading into vesicles which are transported to lysosomes or peroxisomes for degradation, removing damaged proteins and thus preventing mitochondrial dysfunction.

All these processes form part of the protein quality control system of the mitochondrion that is vital for mitochondrial function and cell homeostasis. In this review, we focus specifically on mitochondrial biogenesis and the mtUPR and, in particular, on the implication of mtUPR modulation as a potential treatment of primary and secondary mitochondrial diseases. In addition, we discuss the negative consequences of its activation in cancer patients and its overaction in pathological situations.

Link: https://doi.org/10.3390/ijms24021482

The author of today's open access commentary is quite prolifically opinionated on the topic of mTOR and its status as a central pillar of programmed aging, particularly the hyperfunction version of programmed aging theories. Nonetheless, he sometimes has interesting things to say, as is the case here on the topic of whether aging is a disease. A great deal of ink has been spilled of late on the question of whether or not aging is a disease. This is the case not because everyone suddenly developed an interest in semantics, but rather because it directly affects the regulation of medical development, and thus the flow of funding to research and the later translation of research results into potential therapies.

Programmed aging is roughly the idea that aging is a process under direct natural selection, rather than the mainstream view of aging as a non-selected consequence of natural selection that operates most strongly in early life. In the latter view, early reproductive success near always wins out over a longer reproductive life span, and thus biological systems that offer early life advantage are selected regardless of whether or not they fall apart later in life. Theorists arguing for programmed aging might appeal to group selection, suggesting that aging helps to dampen population explosions, or suggest that aging allows species to outcompete non-aging rivals as the environment changes over long timescales.

Theorizing on programmed aging has gained in popularity in the past decade or so. New strands of thought, such as the hyperfunction theory of programmed aging, in which aging is ascribed to processes of development failing to shut down and running wild in adults, are emerging that incorporate aspects of both programmed and non-programmed theories of aging. For the causal observer, it is becoming a little hard to keep up, particularly as not everyone seems to be arguing for the same version of a given theory, while all using the same name.

Are menopause, aging, and prostate cancer diseases?

Prostate cancer is an age-related disease. Every man would be diagnosed with prostate cancer, except that most men do not live long enough, dying from other age-related diseases. The frequency of prostate cancer detected by autopsy is 30-fold higher than mortality from prostate cancer so that "more men die with prostate cancer than because of it". The older the man, the higher frequency of autopsy-detected prostate cancer. The frequency of high-grade prostate cancer doubles every ten years.

Atherosclerosis is driven by hyperfunction of numerous cell types, acting locally and distantly. Thus, activation of endothelial cells, smooth muscle cells (SMC), and macrophages contributes to the formation of atherosclerotic plaque. Atherosclerosis originates in childhood and progresses throughout life. It occurs in everyone. It is a hallmark of aging and a "normal disease". Clinical manifestations of atherosclerosis, cardiovascular diseases, are the main causes of death in humans.

Some age-related diseases are so program-like that they are considered to be the norm. Menopause happens in every woman, and therefore it is not commonly viewed as a disease. But atherosclerosis and prostate enlargement (and all age-related diseases) also happen in everyone. One may argue that menopause is not as deadly as cancer. However, it is deadlier than osteoarthritis and Alzheimer's disease. Menopause promotes cardiovascular diseases (CVD), osteoporosis, obesity, type II diabetes, and other diseases.

It is difficult to define a disease, especially an age-related disease. For example, osteoporosis and obesity were not officially recognized as diseases until 1994 and 2013, retrospectively. Whether we define age-related alterations as a disease depends on political, cultural, financial, medical, and social reasons. The main objection to considering age-related diseases such as menopause and presbyopia as diseases is that they happen to everyone. However, disease does not need to be rare to be a disease. For example, everyone may be sick with influenza during their lifetime, but it does not make it any less a disease. Furthermore, no definition of disease includes the requirement that it should not affect everyone.

According to conventional views, aging is a risk factor for developing disease. It is believed that aging can be healthy (without diseases) and that humans can die either from aging or from diseases. It was claimed, "aging should be strongly considered not to be a disease and as such should not be treated." According to hyperfunction theory, aging is not a risk factor, aging is the sum of all age-related diseases. In analogy, the zoo consists of animals and does not exist without animals, but the zoo is not an animal. There is no aging without these diseases. So-called "healthy" aging is slow aging observed in centenarians, who develop diseases later in life. But no centenarian dies from old age, all die from age-related diseases.

While looking at the results of this epidemiological study, it is worth noting that height is entangled in the web of correlations that involve socioeconomic status and longevity. Greater height is thought to reduce life expectancy via mechanisms such as (a) greater cancer risk, because more cells in the body means a higher chance of a cancerous mutation occurring in one of those cells, and (b) higher levels of growth hormone. Recall that reduced growth hormone signaling slows aging in mammals. The socioeconomic status benefits of height may offset that, perhaps via a higher status peer group tending to encourage the adoption of better lifestyle choices. These are not large effect sizes in the grand scheme of things, however. Even a poor rejuvenation therapy, or a modest age-slowing therapy would make the effects of height irrelevant.

To date, numerous studies have reported that taller individuals are healthier and live longer. Nevertheless, the association between adult stature and longevity involves conflicting findings. This study investigated whether taller Polish adults live longer than their shorter counterparts. Data on declared height were available from 848,860 individuals who died in the years 2004-2008 in Poland. To allow for the cohort effect, the Z-values were generated. Separately for both sexes, Pearson's r coefficients of correlation were calculated. Subsequently, one way ANOVA was performed.

The correlation between adult height and longevity was negative and statistically significant in both men and women. After eliminating the effects of secular trends in height, the correlation was very weak (r = -0.0044 in men and r = -0.0038 in women) but significant (p = 0.023 and p = 0.022, respectively). On balance, these findings do not bear out the hypothesis that taller individuals have a longevity advantage. Since taller stature had a predictable effect on lifespan in the oldest old (85+), these results strongly suggest that longevity favours smaller people.

We discuss these findings in an attempt to identify the biological mechanisms that might be responsible for greater longevity in smaller people. We also analyze selected anthropological factors that pertain to height and longevity.

Link: https://doi.org/10.5603/fm.a2023.0005

Senescent cells are constantly created and destroyed in the body, but begin to linger with advancing age. The secretions produced by senescent cells are useful in the short term, but increasingly harmful when maintained over the long term, inflammatory and disruptive of tissue structure and function. The production of senolytic drugs to clear senescent cells from aged tissues is an established area of research and clinical development, but is proceeding just as slowly as these matters usually do. The early senolytic combination of dasatinib and quercetin appears quite good, but will not be further developed by industry because these are cheap, off-patent compounds. There is much that could be done by philanthropists to speed up clinical trials, proof of efficacy, and widespread adoption. It is a little ridiculous that the first rejuvenation therapy worthy of the name exists, but very few groups are attempting to advance its adoption.

The emergence of senescent cells in aging people isn't necessarily a problem in and of itself. The problem seems to be that they hang around for too long. Researchers suspect this happens because the immune system in aging individuals isn't up to the task of eliminating them all. And when senescent cells stay put, the cocktail of molecules they produce, and the ongoing immune response, can damage surrounding tissues. Senescence can also contribute to cancer, but the relationship is multifaceted. Senescence itself is a great defense against cancer - cells that don't divide don't form tumors. On the other hand, the molecules senescent cells emit can create an inflamed, cancer-promoting environment

Researchers went hunting for senolytic drugs that would kill senescent cells while leaving their healthy neighbors untouched. They reasoned that since senescent cells appear to be resistant to a process called apoptosis, or programmed cell death, medicines that unblock that process might have senolytic properties. Some cancer drugs do this, and the researchers included several of these in a screen of 46 compounds they tested on senescent cells grown in lab dishes. The study turned up two major winners: One was the cancer drug dasatinib, an inhibitor of several natural enzymes that appears to make it possible for the senescent cells to self-destruct. The other was quercetin, a natural antioxidant that's responsible for the bitter flavor of apple peels and that also inhibits several cellular enzymes. Each drug worked best on senescent cells from different tissues, the scientists found, so they decided to use them both, in a combo called D+Q, in studies with mice.

Scientists have since discovered several other medications with senolytic effects, though D+Q remains a favorite pairing. Further studies from several research groups reported that senolytics appear to protect mice against a variety of conditions of aging, including the metabolic dysfunction associated with obesity, vascular problems associated with atherosclerosis, and bone loss akin to osteoporosis. Despite the excitement, senolytic research remains in preliminary stages. A lot of basic and clinical research must happen first, but if everything goes right, senolytics might someday be part of a personalized medicine plan: The right drugs, at the right time, could help keep aging bodies healthy and nimble. It may be a long shot, but to many researchers, the possibility of nixing walkers and wheelchairs for many patients makes it one worth taking.

Link: https://www.asbmb.org/asbmb-today/science/012923/old-cells-turn-back-the-clock

In the progression of degenerative aging, a process of constant, unresolved inflammatory signaling is one of the most important ways in which low-level molecular damage gives rise to widespread dysfunction of tissue and organs. In today's open access paper, researchers discuss what is known of the way in which the innate immune system reacts to molecular signs of aging, the damage-associated molecular patterns such as DNA debris from dysfunctional mitochondrial and stressed and dying cells. This reaction is amplified by the rest of the immune system into a constant, disruptive state of chronic inflammation that changes cell behavior for the worse and degrades tissue structure and function.

Certain common mechanisms of signaling and regulation, such as the better studied forms of inflammasome, are interesting targets for those seeking to develop therapies to effectively suppress inflammation. The challenge in such efforts has always been to suppress inflammatory signaling in a way that only interferes in excessive inflammation, and not the necessary inflammation required for defense against pathogens, regeneration following injury, and so forth. Existing therapies, such as the biologics used to treat autoimmune conditions, tend to focus on inhibition of specific single signal molecules involved in the inflammatory process, and thus indiscriminately suppress inflammation. There is some hope that targeting inflammasomes will prove to be a better option.

The NLRP3 Inflammasome in Age-Related Cerebral Small Vessel Disease Manifestations: Untying the Innate Immune Response Connection

An inflammasome is a multiple protein complex, comprised of sensor proteins such as pattern recognition receptors (PRRs), an effector protein (i.e., caspase-1 in canonical inflammasome, and an adaptor protein (i.e., apoptosis-associated speck-like protein, ASC, containing a caspase activation and recruitment domain, CARD). An inflammasome modulates the innate immune signaling where PRRs respond to pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs), which results in the activation and accumulation of caspase-1 that cleaves pro-interleukin (IL)-1β and pro-interleukin (IL)-18 to their active forms. The activated pro-inflammatory cytokines modulate inflammation in a series of disorders, including chronic inflammatory disease and neurodegenerative disease.

The pathophysiological basis of cerebral small vessel disease (CSVD) involves changes in the structure and function of cerebral microvasculature that penetrates in deep subcortical regions, such as arteries and/or arterioles as well as lipohyalinosis, microthrombosis, necrosis, and fibrinolysis. CSVD is common with aging and is frequently discovered as an incidental finding after neuroimaging. It is often overlooked by physicians due to its covert nature (i.e., asymptomatic). The neuroimaging manifestation of CSVD includes white matter hyperintensities (WMHs) of presumed vascular origins, enlarged perivascular spaces (ePVS), lacunar infarcts, cerebral microbleed (CMBs), and cortical microinfarcts. Alarmingly, these manifestations account for approximately 25% of the total global cases of ischemic stroke, and over 70% of vascular dementias.

An increase in systemic inflammatory agents such as IL-1β, IL-6, and C-reactive protein (CRP) plays the most important roles in the genesis of neuroinflammation in CSVD and ischemic stroke. The heightened pro-inflammatory agents alongside endothelial dysfunction (i.e., due to the formation and accumulation of cell-derived microparticles and disrupted purinergic signaling) may further aggravate endothelial injury. For example, microthrombi and/or microparticles may aggregate on the endothelial surface, worsening blood-brain barrier (BBB) permeability and leading to microvascular bleeding. Furthermore, inflammation may disrupt cell-cell interactions, exacerbating the cellular injury that results in luminal narrowing, reduced cerebral blood flow, hypoxia, neuronal cell death, and parenchyma damage.

Following parenchyma injury, sequences of pathological changes that ensue could eventually elicit the activation of the NLRP3 inflammasome. The activated NLRP3 inflammasome may further worsen the parenchyma injury through a cascade of inflammatory signaling. As aforementioned, the NLRP3 inflammasome is crucial in the genesis of atherosclerosis, arteriosclerosis, and arteriolosclerosis and increases the likelihood of CSVD and ischemic stroke. Thus, here we hypothesize plausible pathophysiological mechanisms that underlie the NLRP3 inflammasome-linked CSVD through the NLRP3-mediated neuro-thrombo-inflammation, its influence on disease progression and potential therapeutic target.

In our hypothesis, blood-brain barrier (BBB) breakdown caused by elevated thrombo-inflammation, neuronal injury, and activation of neuroglial cells mediates the mitochondrial dysfunction leading to increased production of reactive oxygen species (ROS). ROS activated the NLRP3 inflammasome leading to pyroptosis and secondary neuronal injury that may lead to the development and progression of cerebral small vessel disease (CSVD). Besides, cellular oxidative stress also causes hypoxia-mediated NF-κB pathway activation that subsequently led to NLRP3 inflammasome activation.

An increasingly diverse set of approaches are under development with the aim of measuring biological rather than chronological age. Assessing the age-related burden of damage and dysfunction with sufficient accuracy would enable cost-effective quantification of any potential rejuvenation therapy. It would hopefully steer the research community away from marginal treatments and towards more effective treatments in the near term. Unfortunately, despite a proliferation of such measures, it remains far from clear that any of them can be trusted once one starts in on treating aspects of aging. A given measure of aging may or may not be less sensitive or overly sensitive to the results of a therapy that only addresses one mechanism of aging, but there is no way to know in advance whether or not this is the case without extensive, lengthy calibration in animal and then human studies.

There is no single universal biomarker yet to estimate overall health status and longevity prospects. Moreover, a consensual approach to the very concept of aging and the means of its assessment are yet to be developed. Markers of aging could facilitate effective health control, more accurate life expectancy estimates, and improved health and quality of life. Clinicians routinely use several indicators that could be biomarkers of aging. Duly validated in a large cohort, models based on a combination of these markers could provide a highly accurate assessment of biological age and the pace of aging.

Biological aging is a complex characteristic of chronological age (usually), health-to-age concordance, and medically estimated life expectancy. This study is a review of the most promising techniques that could soon be used in routine clinical practice. Two main selection criteria were applied: a sufficient sample size and reliability based on validation. The selected biological age calculators were grouped according to the type of biomarker used: (1) standard clinical and laboratory markers; (2) molecular markers; and (3) epigenetic markers. The most accurate were the calculators, which factored in a variety of individual biomarkers. Despite their demonstrated effectiveness, most of them require further improvement and cannot yet be considered for use in standard clinical practice.

Link: https://doi.org/10.3390/ijms232315103

Researchers here complain about the term "normal aging", suggesting that it is misleading. There is certainly no shortage of problematic language in the description of aging. "Healthy aging" is a contradiction in terms that is widely used to justify a focus on marginal therapies that cannot even in principle achieve rejuvenation, for example. Does it help progress for language to be aligned with goals? Likely, though perhaps only in the longer term. It is clear that a good portion of the research community is already interested in treating aging as a medical condition, regardless of the language used - but more widespread interest in that goal is always better!

Everyone increases in chronological age once a year, which is considered a normal event and celebrated (or not) on a regular basis. But is there such a thing as normal aging? Normal aging is a descriptive term used frequently in published scientific literature to indicate processes and pathways that similarly change with increasing age in a majority of the population in the absence of overt disease. However, if we take a look beneath the surface, deep into pathological changes that occur in cells with increasing age, nothing appears normal. And in fact, changes become more abnormal with increasing chronological age. So-called "normal" histological changes are considered lesions because they are different from the histology seen at younger ages. Is there such a thing as a normal lesion? We think not, even though many pathologists view the presence of age-related lesions as a normal occurrence for older age groups.

The point of this brief discourse is to provide a convincing argument that the term "normal aging" should not be used because it is scientifically incorrect. Aging consists of abnormal changes that occur over time and in varying degrees in every living creature. In human aging, we know that some individuals are more resilient, so maintain a physically and mentally fit condition with increasing age, while others are less resilient and become increasingly compromised with increasing age. There is thus a tendency to label resilience to aging as normal aging and lack of resilience as abnormal aging. Again, this description lacks scientific merit because changes are still occurring in both resilient and non-resilient groups, but in relative degrees.

Thus, "resilient" aging would be a more correct term to represent a major emphasis on investigating mechanisms and therapeutic targets for resilience, rather than a label of "normal" aging that is misleading and currently receives relatively little attention.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9836033/

The early stages of Alzheimer's disease are characterized by rising levels of amyloid-β in the brain and the formation of misfolded amyloid aggregates. It is presently thought that this is a necessary precursor for the more harmful later stages of the condition, in which chronic inflammation and tau aggregation cause widespread cell death in the brain. It has been noted that amyloid-β exists outside the brain, and there is evidence for levels of amyloid-β in the vasculature to be in dynamic equilibrium with amyloid-β in the brain. Clearing amyloid-β from the bloodstream has shown some promise as an approach to reduce levels in the brain.

You may recall that the misfolded α-synuclein aggregates found in Parkinson's disease are now thought to originate in the gut in a sizable number of patients and thereafter spread to the brain. Analogously, in today's open access paper, researchers present evidence for the gut to provide a significant source of amyloid-β that is transported to the brain via the vasculature. This coincides with the evidence for Alzheimer's patients to have a significantly altered gut microbiome composition. Perhaps this affects the risk of disease via increased microbiome-spurred inflammation, but perhaps it is also generating increased amyloid-β to the point of overwhelming the clearance mechanisms in brain tissue.

In this context, it is worth noting the point that a major route of clearance of molecular waste from the brain is via drainage of cerebrospinal fluid. These drainage pathways become impaired with age, and this may also contribute to a continued imbalance in the generation and clearance of amyloid-β. Further, given that amyloid-β is an antimicrobial peptide, persistent infections may also be involved in increasing levels of amyloid-β. A tipping point exists, and multiple mechanisms may be in play to push a patient into sufficient accumulation of amyloid-β to trigger the onset of Alzheimer's pathology.

Gut-derived β-amyloid: Likely a centerpiece of the gut-brain axis contributing to Alzheimer's pathogenesis

Peripheral β-amyloid (Aβ), including those contained in the gut, may contribute to the formation of Aβ plaques in the brain, and gut microbiota appears to exert an impact on Alzheimer's disease (AD) via the gut-brain axis, although detailed mechanisms are not clearly defined. The current study focused on uncovering the potential interactions among gut-derived Aβ in aging, gut microbiota, and AD pathogenesis.

To achieve this goal, the expression levels of Aβ and several key proteins involved in Aβ metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of Aβ was detected throughout the gut in both mice and human, and gut Aβ42 increased with age in wild type and mutant amyloid precursor protein/presenilin 1 (APP/PS1) mice.

Next, the gut microbiome of mice was characterized by 16S rRNA sequencing, and we found the gut microbiome altered significantly in aged APP/PS1 mice and fecal microbiota transplantation (FMT) of aged APP/PS1 mice increased gut BACE1 and Aβ42 levels. Intra-intestinal injection of isotope or fluorescence labeled Aβ combined with vagotomy was also performed to investigate the transmission of Aβ from gut to brain. The data showed that, in aged mice, the gut Aβ42 was transported to the brain mainly via blood rather than the vagal nerve. Furthermore, FMT of APP/PS1 mice induced neuroinflammation, a phenotype that mimics early AD pathology.

Taken together, this study suggests that the gut is likely a critical source of Aβ in the brain, and gut microbiota can further upregulate gut Aβ production, thereby potentially contributing to AD pathogenesis.

Endothelial dysfunction in blood vessel walls is thought to precede many of the other issues of vascular aging, promoting the development of atherosclerosis and loss of regulation of contraction and dilation of blood vessels. Researchers here investigate the degree to which inflammatory signaling and cellular senescence in the context of endothelial aging may be regulated by one specific signaling pathway.

Protein kinase R (PKR) plays an important role in regulating various signal pathways of innate immune diseases. In the past, it was considered that PKR could only be activated by infectious agents, toll-like receptor ligands, cytokines, and other inherent immune-related factors, to regulate the activation of immune signal pathways and release of immune inflammatory factors. In our recent studies, PKR has been revealed to be a key target in promoting endothelial cell senescence and pulmonary hypertension mediated endothelial injury.

In normal physiological conditions, the endothelium is a crucial regulator of vascular physiology and produces several substances to protect the layer of arteries. However, injured endothelial cells become the initial contributor to promote the development of cardiovascular diseases in a pathological phenotype. We previously reported that PKR triggered IL-1β and HMGB1 release to induce PH development, although how endothelial PKR promotes IL-1β and HMGB1 release in vascular aging still need to be further investigated.

We try to in-depth evaluate whether PKR mediated inflammatory factors release is because of mediating endothelial cell hyperactivation. Despite this, how endothelial PKR-mediated inflammatory factors release induces vascular smooth muscle cells (VSMCs) senescence is still unknown. As the main cell type within the vasculature, VSMCs are responsible for maintaining vascular homeostasis. It can present as contraction phenotype and secretory phenotype.

The phenotype transforming of VSMCs from contraction phenotype to secretory phenotype is a remarkable symbol of vascular aging. In normal blood vessel, contraction phenotype VSMCs is the vast majority type of VSMCs. During the aging process, VSMCs gradually lose the contractile phenotype and acquire the proliferative and secretory phenotype, which eventually contributes to vascular degeneration and vascular remodeling via abnormal self-proliferation and promotes the vascular stiffness by the excessive deposition of collagen and decrease of elastin. Therefore, we hypothesize that endothelial PKR-mediated inflammatory factors release can induce the phenotype transforming of VSMCs to induce vascular aging.

Global knockout of PKR exhibits significantly delayed vascular aging compared to wild-type mice at the same age. In vitro, using PKR siRNA or the cell hyperactivation inhibitor glycine or disulfiram can effectively inhibit H2O2 or palmitic acid-induced endothelial cell hyperactivation, IL-1β and HMGB1 release, and co-cultured VSMC phenotype transforming. These results demonstrate that endothelial PKR activation induces endothelial cell hyperactivation to release HMGB1 and IL-1β, which promotes the phenotype transforming of VSMC and subsequent accelerates the process of vascular aging.

Link: https://doi.org/10.1016/j.isci.2022.105909

It is known that the practice of calorie restriction slows the characteristic loss of muscle mass and strength that takes place with age, leading to sarcopenia. Researchers here identify a mechanism by which lowered calorie intake improves muscle stem cell activity in the context of aging. Other work suggests that declining stem cell activity is the most important factor in the development of sarcopenia. An understanding of the mechanisms involved may lead to improved ways to mimic the specific protective effects of calorie restriction in this context.

In this study, we used a calorie restriction (CR) model of elderly mice with muscle-specific 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) knockout mice and 11β-HSD1 overexpression mice to confirm that CR can delay muscle aging by inhibiting 11β-HSD1 which can transform inactive glucocorticoid (cortisone) into active glucocorticoid (cortisol). The ability of self-renewal and differentiation into muscle fibers of these mouse muscle stem cells (MuSCs) was observed in vitro. Additionally, the mitochondrial function and mitochondrial ATP production capacity of MuSCs were measured by mitochondrial oxygen consumption.

It was found that the 11β-HSD1 expression level was increased in age-related muscle atrophy. Overexpression of 11β-HSD1 led to muscle atrophy in young mice, and 11β-HSD1 knockout rescued age-related muscle atrophy. Moreover, CR in aged mice reduced the local effective concentration of glucocorticoid through 11β-HSD1, thereby promoting the mitochondrial function and differentiation ability of MuSCs.

Together, our findings highlight promising sarcopenia protection with CR in older ages. Furthermore, we speculated that targeting an 11β-HSD1-dependent metabolic pathway may represent a novel strategy for developing therapeutics against age-related muscle atrophy.

Link: https://doi.org/10.3389/fmed.2022.1027055

Visceral fat tissue is known to produce chronic inflammation via a range of mechanisms that rouse the immune system to futile, self-defeating action. Here researchers investigate the signals produced by macrophages of the innate immune system in fat tissue and their contribution to the progression of atherosclerosis. Atherosclerosis is the buildup of fatty deposits in blood vessel walls, the largest single cause of human mortality. It is a condition driven by macrophage dysfunction, as macrophages are responsible for clearing excess cholesterol, toxic forms of altered cholesterol, and cholesterol carriers such as LDL particles from blood vessel walls. The degree to which macrophages falter at this task determines the tipping point at which a small amount of cholesterol deposition can grow to become an atherosclerotic plaque.

One of the factors determining macrophage activity is their response to the signaling environment. Macrophages can adopt a variety of states depending on levels of various inflammatory signal molecules. The most useful state for clearing cholesterol is M2, an anti-inflammatory, pro-regenerative collection of behaviors. Inflammatory signaling tends to make macrophages adopt the aggressive M1 state optimized for hunting down pathogens, however, and these macrophages give up on cholesterol clearance. Thus the more inflammation, the less effort goes into to attempting to repair atherosclerotic lesions and the cholesterol deposits that will become atherosclerotic lesions.

In today's open access paper, researchers identify some of the more important signals emerging from macrophages in visceral fat tissue. They note that blocking these signals can remove the effects of fat tissue on the progression of atherosclerosis. A more practical approach is to avoid becoming overweight in the first place, but it is worth noting that as aging progresses, a state of chronic inflammation will arise regardless; visceral fat just makes it considerably worse. Solving the underlying causes of that chronic inflammation will be necessary. Even blocking the important signals is only a patch on the problem, and a patch that also tends to disable some of the necessary working of the immune system following injury and infection. That is not ideal!

Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis

Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr-/- recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors.

By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.

The quality of data resulting from studies of exercise and disease risk has increased greatly since the advent of low-cost accelerometer devices. Self-reported activity data has many issues, not least of which being the challenge of assessing just how much low intensity activity is actually taking place. Nonetheless, the evidence for a greater degree of physical activity to reduce the risk of age-related disease was extensive even prior to the commonplace use of accelerometers in such studies, and has only grown since. The example here is one of a great many studies focused on exercise in the context of dementia risk.

Because few large studies have examined device measures of movement and sitting in relation to mild cognitive impairment and dementia, much of the published research on the associations of physical activity and sedentary behavior with cognitive decline and dementia is based on self-reported measures. For this study, the researchers sampled data from 1,277 women as part of two Women's Health Initiative (WHI) ancillary studies - the WHI Memory Study (WHIMS) and the Objective Physical Activity and Cardiovascular Health (OPACH) study. The women wore research-grade accelerometers and went about their daily activities for up to seven days to obtain accurate measures of physical activity and sitting.

The activity trackers showed the women averaged 3,216 steps, 276 minutes in light physical activities, 45.5 minutes of moderate-to-vigorous physical activity and 10.5 hours of sitting per day. Examples of light physical activity could include housework, gardening or walking. Moderate-to-vigorous physical activity could include brisk walking. The researchers reported that, among women aged 65 or older, each additional 31 minutes per day of moderate-to-vigorous physical activity was associated with a 21 percent lower risk of developing mild cognitive impairment or dementia. Risk was also 33 percent lower with each additional 1,865 daily steps. The study findings also showed that higher amounts of sitting and prolonged sitting were not associated with higher risk of mild cognitive impairment or dementia.

Link: https://today.ucsd.edu/story/more-steps-moderate-physical-activity-cuts-dementia-cognitive-impairment-risk

Long term treatment of mice that results in a modest extension of life span, such as the example here involving inhibition of a subunit of PI3K, is unlikely to be interesting as a basis for human medicine to target aging. Life span is more plastic in short-lived mammals in response to altered metabolic states. Of the known approaches to slowing aging where one can compare humans and mice directly, there is no large extension of life in humans. The most interesting approaches to aging are those that can be applied very intermittently later in life, and which repair damage or enhance function sufficiently well for even one treatment to improve matters noticeably. Senolytics or the restoration of stem cell and immune function following the use of CASIN, for example.

Treatment of healthy mice from middle-age (one year) with alpelisib, a cancer drug that targets the p110α subunit of an enzyme called PI3K, can increase their lifespan by an average of ten percent. In this study, mice were fed a control diet or the same diet with the addition of a drug called alpelisib. Not only did the mice fed the drug containing diet live longer, they showed some signs of being healthier in old age such as improved coordination and strength. However, the researchers are cautious about application to humans since the mice treated with the drug also had some negative markers of ageing like lower bone mass.

"We are not suggesting that anyone should go out and take this drug long-term to extend lifespan, as there are some side effects. However, this work identifies mechanisms crucial to ageing that will be of use in our long-term efforts to increase lifespan and health-span. It also suggests a number of possible ways in which shorter term treatments with this drug could be used to treat certain metabolic health conditions and we are following this up now."

Link: https://www.auckland.ac.nz/en/news/2023/01/25/scientists-identify-drug-that-could-extend-lifespan.html