Fight Aging!

Prizes for success in research and development can work well, if coupled with suitable publicity and activism. Such efforts have a long history, going back to the well-documented longitude rewards offered by the British government in the 1700s. More recently, the original Ansari X Prize for suborbital flight was a very successful example of this sort of initiative, and was launched around the same time as the Methuselah Mouse Prize to spur greater efforts to extend life in animal models. The Palo Alto Longevity Prize followed later with similar goals. Unfortunately for the ability of longevity-focused prizes to generate ongoing publicity, it has turned out to be hard to beat the 60-70% extension of life of mice lacking functional growth hormone signaling. That was not anticipated.

XPRIZE is the foundation that emerged from the original Ansari X Prize, set up to run further incentive prizes for research and development. After a few years of recent interest in involving XPRIZE to in some way help to accelerate the ongoing development of means to treat aging, organizers have now found the sizable funding needed for such an effort, and launched the XPRIZE Healthspan initiative. Development of medical interventions and clinical trials to prove their efficacy are expensive propositions, and a prize to incentivize more activity in this arena must be correspondingly large - and so it is.

XPRIZE Launches Larges Competition in History - $101M XPRIZE Healthspan to Drive Healthier Aging for All

XPRIZE, the world's leader in designing and operating large-scale incentive competitions to solve humanity's grand challenges, today launches $101M XPRIZE Healthspan. This 7-year global competition is the largest competition in history and the largest XPRIZE to date, offering $111 million total between the prize purse and a bonus award. XPRIZE Healthspan will award $101 million in prize funding to the team who successfully develops a proactive, accessible therapeutic that restores muscle, cognition, and immune function by a minimum of 10 years, with a goal of 20 years, in persons aged 65-80 years, in one year or less. An additional $10M FSHD Bonus Prize will be awarded to a team that demonstrates the ability to restore lost muscular function due to Facioscapulohumeral Muscular Dystrophy (FSHD) in one year or less.

XPRIZE Healthspan is the first health-focused competition of its kind, incentivizing competing teams to develop a single or combination of therapeutic treatments that will restore muscle, brain, and immune function lost to age-related degradation by at least 10 years, with a goal of 20 years. The finalist teams competing for XPRIZE Healthspan will conduct 1-year clinical trials. These trials will include persons who are aged 65-80 years who are generally healthy and free of major chronic disease or disability but who are experiencing mild age-related declines in function. For example, slowing walk speed, ability to rise from a chair, or mild changes in memory or cognition. The specific criteria are based on data from multiple sources, and indicate higher risk for future mobility disability, Alzheimer's disease, and related dementias, and multiple age-related diseases such as cardiovascular disease and cancer.

Focusing on multiple measures of healthspan rather than the one absolute measure of life span, and focusing on people rather than mice, is a logical reaction to what has been learned in the past few decades about mouse aging and a greater appreciation of the differences in the response to interventions targeting metabolism in mice and humans. Short-lived species exhibit a much greater extension of life span from calorie restriction and loss of growth hormone signaling than is the case in long-lived species, but the short-term improvements in health and metabolism appear much the same.

By the way functions are commonly measured, it might be possible to hit the prize minimum threshold of a 10 year reversion of measures of aging in at least muscle function via resistance exercise. If one starts with sedentary older people, much more likely! This may be intentional, in the sense that trying to improve on the size of the benefits produced by exercise should be a focus for the research and development community, but many of the interventions currently under development do not outperform exercise, and nobody is really holding anyone's feet to the fire on that topic.

The XPRIZE site does not appear to yet include a description of the specific measures they wish to use to assess the quality of an intervention in each of muscle function, cognitive function, and immune function, but a variety of different measures exist, some standardized, some not. It is unclear as to whether the prize organizers will leave it to the teams to pick their own measures. There is certainly a lot of room to argue over which measures are most appropriate.

Researchers here demonstrate that means of mildly inhibiting the production of some of the protein machinery used to generate chemical energy store molecules, adenosine triphosphate, in mitochondria can extend life by 50-70% in nematode worms - a species in which much larger life extension is possible, so this might be viewed as a moderate effect size. Many different approaches to adjusting mitochondrial function can slow aging and extend life in short-lived species. In some cases this works by provoking mitochondria into an alternative pathway for ATP generation that produces a little more oxidative stress than usual, triggering greater cell maintenance activities. The details and dosing matter, however, and there is a fine line between lesser disruption that slows aging versus greater disruption that causes cell and tissue dysfunction to accelerate aging.

Aging is a continuous degenerative process caused by a progressive decline of cell and tissue functions in an organism. It is induced by the accumulation of damage that affects normal cellular processes, ultimately leading to cell death. It has been speculated for many years that mitochondria play a key role in the aging process. In the aim of characterizing the implications of mitochondria in aging, here we used Caenorhabditis elegans (C. elegans) as an organismal model treated a panel of mitochondrial inhibitors and assessed for survival. In our study, we assessed survival by evaluating worm lifespan, and we assessed aging markers by evaluating the pharyngeal muscle contraction, the accumulation of lipofuscin pigment, and ATP levels.

Our results show that treatment of worms with either doxycycline, azithromycin (inhibitors of the small and the large mitochondrial ribosomes, respectively), or a combination of both, significantly extended median lifespan of C. elegans, enhanced their pharyngeal pumping rate, reduced their lipofuscin content and their energy consumption (ATP levels), as compared to control untreated worms, suggesting an aging-abrogating effect for these drugs. Similarly, diphenyleneiodonium chloride (DPI), an inhibitor of mitochondrial complex I and complex II, was capable of prolonging the median lifespan of treated worms. On the other hand, subjecting worms to vitamin C, a pro-oxidant, failed to extend C. elegans lifespan and upregulated its energy consumption, revealing an increase in ATP level. Therefore, our longevity study reveals that mitochondrial inhibitors (i.e., mitochondria-targeting antibiotics) could abrogate aging and extend lifespan in C. elegans.

Link: https://doi.org/10.18632/aging.205229

Many seemingly unrelated aspects of aging correlate with one another in incidence and progression. All of the myriad manifestations of degeneration aging arise from the same small set of underlying processes of cell and tissue damage, so such correlations are perhaps unsurprising. There are cases in which a direct causal connection is found, as in the case of hearing loss contributing to dementia, but in the case of hearing loss and frailty we might expect correlation to arise from shared underlying mechanisms, such as the chronic inflammation that is characteristic of later life.

In a nationally representative sample of older adults in the U.S., worse hearing continuously was associated with greater odds of being frail and pre-frail versus robust after adjusting for sociodemographic and health characteristics. Across hearing categories, those with moderate or greater hearing loss had 84% and 46% greater odds of being frail and pre-frail versus robust, respectively, compared to those with no hearing loss. In age-stratified analyses, the association of worse hearing with being frail versus robust remained significant among older adults aged 71-80 only. Furthermore, lack of hearing aid use was associated with greater odds of being frail and pre-frail versus robust, and frail versus pre-frail.

How hearing loss may be linked to frailty in older adults is not clear. Hearing loss impairs encoding of sound resulting in difficulty with communication and hinders spatial awareness. This may eventually lead to cognitive and physical decline via constantly high cognitive load due to effortful listening, greater risk for social isolation, and depression, and a poorer physical function profile including slower gait speed, lower levels of physical activity, and more falls. Furthermore, these manifestations may negatively impact and reinforce one another in a vicious cycle. For example, hearing loss may cause social withdrawal which in turn may contribute to physical decline and more social withdrawal. Therefore, the underlying mechanisms potentially linking hearing loss to frailty may be related to cognitive and physical decline. Interestingly, we found that the studied associations were stronger among participants ages 71-80 years, suggesting that hearing loss at a relatively younger age may have a greater impact on frailty risk.

Link: https://doi.org/10.1186/s12877-023-04465-1

16s rRNA sequencing allows the microbial populations resident in the gut to be catalogued in detail: which species are present, and relative numbers by species. In the years since this assay became cheap, reliable, and readily available, researchers have built increasingly large human gut microbiome databases from samples obtained over the course of epidemiological studies. The research community has found that the gut microbiome exhibits characteristic differences in older people, marked by a growth in populations of inflammatory microbes and a loss of those species that produce beneficial metabolites. Further, some age-related conditions appear to be strongly correlated with an altered gut microbiome, particularly with the presence of increased numbers of inflammatory microbes.

Alzheimer's disease is one of the conditions for which a growing body of evidence indicates that an altered gut microbiome plays a role in the onset and progression of pathology. The most likely mechanism by which the gut microbiome can contribute to disease is via provoking an increase level of chronic inflammatory signaling. Unresolved, continual inflammation is a characteristic of aging. It is disruptive of cell and tissue function, and contributes to many different age-related conditions. This doesn't rule out other possibilities, as biology is complex, and the gut microbiome can generate harmful metabolites as well as beneficial ones, but as today's open access paper indicates, inflammation is the first place to look.

Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study

Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity.

Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using 11C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants.

Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.

Researchers here note correlations between hearing loss and specific microstructural changes in the brain indicative of loss of function. Evidence from studies involving patients with and without hearing aids suggests that hearing loss accelerates age-related neurodegeneration. Depriving the brain of sensory processing activity may produce maladaptive compensatory changes, or may simply be a case of "use it or lose it", as is the case for muscle tissue. The mechanisms involved are not yet fully understood, and the situation is complicated by underlying processes of aging that contribute separately to dysfunction in both the brain and the auditory system.

Hearing loss affects more than 60 percent of adults aged 70 and older in the United States and is known to be related to an increased risk of dementia. Researchers employed hearing tests and magnetic resonance imaging (MRI) to determine whether hearing impairment is associated with differences in specific brain regions. Individuals enrolled in this observational study who had hearing impairment exhibited microstructural differences in the auditory areas of the temporal lobe and in areas of the frontal cortex involved with speech and language processing, as well as areas involved with executive function.

"These results suggest that hearing impairment may lead to changes in brain areas related to processing of sounds, as well as in areas of the brain that are related to attention. The extra effort involved with trying to understand sounds may produce changes in the brain that lead to increased risk of dementia. If so, interventions that help reduce the cognitive effort required to understand speech - such as the use of subtitles on television and movies, live captioning or speech-to-text apps, hearing aids, and visiting with people in quiet environments instead of noisy spaces - could be important for protecting the brain and reduce the risk of dementia."

Link: https://today.ucsd.edu/story/hearing-loss-is-associated-with-subtle-changes-in-the-brain

The incentives placed upon medical development ensure that far too much attention is given to ways in which established, existing drugs can be reused in other contexts, even given marginal effect sizes. It is much cheaper to repurpose an existing drug to a marginal new use than it is to build an actually effective new drug. To the extent that aging becomes a popular target for drug development, and one might argue that this is in the process of happening, every existing drug is going to be scrutinized in this context. Anti-diabetic drugs in particular seem to receive a lot of attention for potential marginal ability to slow aging in some way.

Here we propose that SGLT2 inhibitors (SGLT2i), a class of drugs primarily used to treat type 2 diabetes, could also be repositioned as anti-aging senomorphic drugs (agents that prevent the extrinsic harmful effects of senescent cells). As observed for metformin, another anti-diabetic drug with established anti-aging potential, increasing evidence suggests that SGLT2i can modulate some relevant pathways associated with the aging process, such as free radical production, cellular energy regulation through AMP-activated protein kinase (AMPK), autophagy, and the activation of nuclear factor (NF)-kB/inflammasome. Some interesting pro-healthy effects were also observed on human microbiota.

All these mechanisms converge on fueling a systemic proinflammatory condition called inflammaging, now recognized as the main risk factor for accelerated aging and increased risk of age-related disease development and progression. Inflammaging can be worsened by cellular senescence and immunosenescence, which contributes to the increased burden of senescent cells during aging, perpetuating the proinflammatory condition. Interestingly, increasing evidence suggested the direct effects of SGLT-2i against senescent cells, chronic activation of immune cells, and metabolic alterations induced by overnutrition (meta-inflammation). In this framework, we analyzed and discussed the multifaceted impact of SGLT2i, compared with metformin effects, as a potential anti-aging drug beyond diabetes management. Despite promising results in experimental studies, rigorous investigations with well-designed cellular and clinical investigations will need to validate SGLT2 inhibitors' anti-aging effects.

Link: https://doi.org/10.1016/j.arr.2023.102131

The practice of calorie restriction, eating up to 40% fewer calories while structuring the diet to continue to obtain sufficient micronutrients, is well demonstrated to slow aging and extend life in short-lived species. It is thought that the primary mechanism for this effect is upregulation of the cellular maintenance process of autophagy, given that sabotaging autophagy prevents extension of life span resulting from calorie restriction. Calorie restriction produces such sweeping changes in cell and tissue function that there remains plenty of room to argue for other mechanisms to be important, however. For example, we might consider the loss of visceral fat mass as likely a sizable contribution, given that visceral fat promotes chronic inflammation, and surgically removing visceral fat from mice produces significant benefits.

Calorie restriction is thought unlikely to produce sizable gains in human life span, on the grounds that this would have become well known in ancient times if it was the case. Calorie restriction has been formally assessed in humans in recent years. In the short-term, health benefits look quite similar to those produced in mice. Over the longer term, data is lacking. The longest and largest formal study today was the second phase of the CALERIE trial, in which 128 participants underwent two years of an average 12% calorie restriction compared to the 71 control participants. This study produced a great deal of data that continues to be mined for insights into human aging and effects of calorie restriction in a long-lived species such as our own, to contrast with the sizable effects on health and longevity in short-lived species such as mice.

In particular, and the topic for today, cellular senescence and its role in degenerative aging has garnered far greater interest in the research community in the years since the CALERIE study took place. Thus in today's open access paper, scientists examine CALERIE study data to find evidence for calorie restriction to reduce the burden of cellular senescence that is characteristic of aging. It is known that calorie restriction reduces the burden of senescent cells in mice. The CALERIE data is not as convincing, however. This is probably because the participants were largely not old enough to have a sizable number of senescent cells present in their tissues. It is also the case that other researchers have found it hard to correlate levels of circulating proteins known to be generated by senescent cells with senescent cell burden, for reasons yet to be fully explored.

Calorie restriction reduces biomarkers of cellular senescence in humans

Compelling evidence from a wide range of animal studies suggests that calorie restriction (CR) with adequate nutrient intake is a promising strategy to extend lifespan and delay the onset of several age-related chronic diseases. In humans, the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) has been the most rigorous study to investigate the effects of CR. Phase 2 of CALERIE was a 2-year, multicenter, randomized controlled trial in healthy non-obese young-to-middle-aged individuals to examine the safety and effects of moderate CR compared to an ad libitum (AL) diet on predictors of longevity, disease risk factors, and quality of life. Although the average CR attained over the 2 years was ~12% rather than the prescribed 25%, the intervention was deemed safe and effective in promoting cardiometabolic risk reduction. The long-term implications of the intervention on healthspan and longevity remain to be established, but the biospecimens collected during the CALERIE study represent a unique resource to explore the influence of CR on the biology of aging in humans.

In this study we found that 2 years of moderate CR with adequate nutrient intake compared to AL significantly decreased the circulating levels of several senescence-associated biomarkers in healthy, young to middle-aged individuals without obesity. A greater number of biomarkers were modulated at 12 months than at 24 months, but PAI1, PARC, TARC, and TNFR1 were lower in CR participants at both timepoints. Using a machine learning approach, we observed that the changes in several biomarkers were important predictors of the change in CALERIE metabolic outcomes, including HOMA-IR, insulin sensitivity index, and resting metabolic rate residual. Our results advance the mechanistic understanding of CR and suggest a potential link between cellular senescence and metabolic health in humans.

Previous findings from the CALERIE study evidenced a reduction in systemic markers of inflammation, such as C-reactive protein, in participants randomized to the CR intervention. Low grade "sterile" systemic inflammation is considered a risk factor for several age-related chronic diseases and, although its pathogenesis is multifactorial, senescent cells through their senescence-associated secretory phenotype (SASP) are a plausible source of proinflammatory molecules. Unfortunately, none of the SASP components studied to date is unique to senescent cells and, certainly, the secretome of other cell types may be affected by CR. At this time, however, we cannot disentangle whether the reduced levels in circulating senescence-related biomarkers observed in response to CR reflect reduced senescent cell accumulation, increased clearance, or inhibition of their SASP. It is also not clear what organs are the main targets of the intervention. Results from our in silico analysis would suggest that CR may target senescent cells in adipose tissue, but the small sample size limits the generalizability of these results.

To corroborate our data demonstrating a reduction in circulating senescence biomarkers in response to CR, we examined tissue-level changes in a recently defined gene set of 125 secreted factors, transmembrane proteins, and intracellular proteins centered on cellular senescence and the SASP, named SenMayo. Through gene set enrichment analysis we observed a significant reduction in SenMayo in response to CR, which is reflected by an enrichment at baseline compared to 12 months. We note that we did not detect a significant change by RNA sequencing in expression of CDKN1A (P21) or CDKN2A (P16), two prototypical markers of cellular senescence. This may be related to their variable and low levels of expression, particularly in younger and healthier adults.

Standard approaches to generating aging clocks from biological data produce algorithmic combinations of factors that are opaque. It is entirely unclear as to how they relate to underlying mechanisms of damage and dysfunction that produce degenerative aging, and thus hard to use them as a tool to assess ways to modify those mechanisms. Explainable artificial intelligence is a term of art used to describe approaches to machine learning that produce more insight into how the final product actually works, what factors went into its construction, how it relates to underlying processes. Given that the primary challenge in the field of measuring biological age, such as via epigenetic clocks, is that we don't understand how these clocks relate to specific causes and processes of aging, it seems sensible to make more of an effort to produce aging clocks that are comprehensible from the outset. The work here is a step in that direction.

Existing biological age clocks have three main limitations. First, they necessitate a trade-off between accuracy (ie, predictive performance for chronological age or mortality) and interpretability (ie, understanding each feature's contribution to the prediction). Most of them use linear models that offer interpretability but weaker predictive power for mortality prediction than complex machine-learning models. This choice is natural given that interpretability is a key goal of biological age clocks: identifying biomarkers of biological age can improve our understanding of the ageing process and help develop drugs that target ageing-related dysfunction. Although advanced machine-learning models have created first-generation biological age models using diverse data types such as epigenetic features, blood markers, electrocardiogram features, brain MRI features, and transcriptomic features, these models are hard to interpret and do not have individualised explanations. To build models that are both accurate and interpretable, we turn to the emerging area of explainable artificial intelligence (XAI).

The second limitation is that interpretations of previous biological age clocks might not address important scientific questions. Previous biological age studies primarily explain the model as a whole (global explanation). However, given the substantial variations in ageing processes among individuals, individualised explanations are crucial for comprehending complex ageing mechanisms. We leveraged recent XAI methods to provide principled individualised (local) explanations on the basis of feature attributions. Typically, feature attributions can be difficult to understand for non-machine-learning practitioners because they are usually in units of predicted probability or logits units. To make our biological age explanations more accessible, we rescaled our attributions to the age scale in units of years so that the rescaled attributions sum to the biological age acceleration (AgeAccel) of an individual.

The third limitation of current biological age clocks is their inability to incorporate several age-related outcomes, such as cause-specific mortalities. Their inability to account for these factors restricts our understanding of important features for different ageing processes. This shortcoming is problematic because biological ageing is enormously complex and thought to be driven by many biological processes. Previous studies noted low agreement between biological age clocks in terms of their correlations with each other and associations with ageing traits, implying that they measure different aspects of biological age. To solve this, we developed our biological age clocks by predicting diverse age-related outcomes, such as specific mortalities and morbidities, allowing us to target and specify particular underlying ageing mechanisms that our clocks capture.

Here we introduce ExplaiNAble BioLogical Age (ENABL Age), a new approach to estimate and interpret biological age that combines complex machine learning and XAI methods. We performed a comprehensive validation of ENABL Age using the UK Biobank and National Health and Nutrition Examination Survey (NHANES) datasets, assessing its ability to capture ageing mechanisms and offering concrete examples of its interpretability.

Link: https://doi.org/10.1016/S2666-7568(23)00189-7

It is becoming clear that there are correlations between the composition of the gut microbiome and risk of suffering neurodegenerative conditions such as Parkinson's disease and Alzheimer's disease. The gut microbiome changes with age, the populations of inflammatory microbes growing in size, while microbes that create beneficial metabolites are diminished in number. Even only considering the effects of additional chronic inflammation in later life, it is clear that a more inflammatory gut microbiome is harmful. There may be other ways in which gut-resident microbes can contribute to neurodegenerative conditions, however. Finding associations is just the start of the research process, but it does indicate that greater emphasis should be placed on the known ways to restore a youthful balance of microbes in the gut, such as fecal microbiota transplantation.

Researchers conducted a comprehensive analysis of all of the genetic material found in the gut of 420 participants from two large epidemiological studies - the Nurses' Health Study and the Health Professionals Follow-Up Study. They found a consistently lower abundance of certain types of anti-inflammatory, anaerobic bacteria in people with Parkinson's disease. This change was also noticeable among study participants who experienced early signs of Parkinson's disease, which can predate the onset of the classic motor symptoms by many years.

"These species of bacteria are known for their role in reducing inflammation in the gut. This depletion supports a potential link between gut inflammation and Parkinson's disease (PD). The fact that we see these changes before a PD diagnosis suggests that, in the future, the gut microbiome may serve as a biomarker for identifying the earliest phases of PD. This has the potential to revolutionize the diagnosis and treatment, as early detection is often key to developing new therapies."

Researchers are now turning their attention to new research that examines the connection between the microbiome and Alzheimer's disease. The brain disorder slowly destroys memory, thinking skills and, eventually, the ability to carry out the simplest tasks. Researchers are conducting the largest comprehensive study of the microbiome in Latinos to better understand the link between the gut microbiome and Alzheimer's disease. The researchers will study participants in the ongoing Boston Puerto Rican Health Study (BPRHS), a long-term research project launched in 2004. With updated cognitive assessments and the analysis of MRI brain scans and blood and stool samples, the research team will identify the gut composition in each participant, the function of each species of bacteria, and any harmful molecules that could cause disruption in the brain.

Link: https://www.uml.edu/news/stories/2023/microbiome-brain.aspx

A cell can enter a senescent state in response to various forms of damage and stress, including the short telomeres that occur when reaching the Hayflick limit on cellular replication. A senescent cell ceases to replicate and secretes pro-inflammatory signals, attracting the attention of the immune system. Senescent cells help to suppress cancer by pointing the immune system to areas of potential risk in tissue, and are a part of the response to injury, aiding in regeneration. Senescent cells are normally destroyed by the immune system shortly after creation, but the pace of destruction slows down with age, allowing the number of lingering senescent cells to increase over time. The signals that are helpful in the short term become harmful when present constantly for the long term, disrupting tissue function.

Senolytic therapies are those that can selectively destroy senescent cells, and seem the most straightforward approach to treating this contribution to degenerative aging. Animal studies in which senescent cells are destroyed have demonstrated a rapid, sizable reversal of many measures of aging and age-related disease. The data is impressive. Researchers are looking into other approaches, though, such as suppression of inflammatory signaling or prevention of the senescent state, under the general heading of senotherapeutics. Proteomic analysis plays a sizable role in this area of research and development, as noted in today's open access paper. While first generation senolytic drugs are being tested at some pace in the clinic, largely the dasatinib and quercetin combination, readily available to many via off-label prescriptions, very little effort is spend on that in comparison to the search for novel ways to destroy or change the behavior of senescent cells. This is unfortunate; more of an effort should be made to determine whether existing, low-cost senolytics could be highly beneficial in human patients.

Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies

Aging comprises a cascade of underlying cellular and molecular processes, commonly referred to as the hallmarks of aging, that lead to a gradual loss of function and increased susceptibility to diseases. One of the most studied hallmarks of aging, cellular senescence, is a key driver of aging and age-related diseases. Cellular senescence is a complex stress response resulting from a variety of sub-lethal stresses that permanently alter the state of a cell. Three of the defining features of senescence are a permanent arrest of cell proliferation, an increased secretion of a variety of bioactive molecules known as the senescence-associated secretory phenotype (SASP), and a resistance to apoptosis. Despite an arrest of cell growth, senescent cells remain metabolically active and secrete a robust SASP that comprises bioactive molecules, including metabolites, proteins, and lipids. The chronic presence of senescent cells and the SASP are connected to various age-related disorders such as cancer, diabetes, neurodegeneration, osteoarthritis, and cardiovascular disease. Therefore, the elimination of senescent cells and the SASP are promising approaches for combating age-related diseases and improving healthspan.

Causal linkage among aging, cellular senescence, and age-related diseases has caused the emergence of 'senotherapeutics', a catch-all term that refers to therapeutic interventions that target senescent cells. Two common classes of pharmacological senotherapeutics include senolytics and senomorphics. Senolytics are chemical compounds that selectively kill senescent cells. Non-pharmacological senotherapeutic approaches, such as vaccines or immunotherapies, are also proposed options for the selective elimination of senescent cells. Interventions that reduce the upstream inducers of senescence, such as DNA damage, ROS, inflammation, or metabolic imbalance, likely confer senotherapeutic benefits by reducing the initiation of senescence. Additionally, targeting cell populations that drive senescence, such as aged immune cells, may reduce senescent cell burden. Senomorphics are the agents that can block or otherwise modulate the SASP to reduce its detrimental activity and mitigate aging phenotypes. The discovery of the SASP and its potency as a driver of aging have greatly increased interest in its comprehensive characterization, both to explore new mechanisms of aging and identify new biomarkers that indicate 'senescence burden', a useful metric for the clinical translation of senotherapeutic approaches.

Protein biomarkers are essential due to their diagnostic, prognostic, and predictive power, as well as identifying and stratifying patients for treatment and measuring the efficacy of therapies. Mass spectrometry-based proteomics is a powerful, versatile, and robust technology used for comprehensively quantifying and discovering proteins with unrivaled specificity. Given the robust and heterogeneous proteomic phenotypes associated with senescence and the SASP, the discovery and profiling of their proteomic signatures require the large-scale, unbiased, and quantitative abilities that mass spectrometry can provide. The presence of senescence-associated proteins in circulation in recent studies also suggests the use of proteomic technologies will be required for the detection and quantification of senescence biomarkers in blood. Numerous innovations in mass spectrometry workflows for biomarker and drug discovery have been made in recent years, opening new opportunities to accelerate the development of senotherapeutics.

Here, we review the available technologies for identifying, validating, and prioritizing protein biomarkers and therapeutic targets identified via mass spectrometry and how these technologies may be leveraged for the clinical translation of senotherapeutics. We describe the technological advancements that have enabled researchers to address challenges inherent to the proteomic analysis of blood, such as the wide dynamic range of protein concentrations, and discuss multiple workflows that can be leveraged for the discovery of senescence biomarkers, senolytic targets, and cell-surface proteins. We also highlight how modern mass spectrometry-based technologies will open the door for future clinical applications, develop translationally relevant approaches to quantify aging and cellular senescence, and develop therapeutics for enhancing human healthspan.

The Amaranth Foundation is one of a small number of organizations created by high net worth individuals to accelerate progress towards the development of therapies to treat aging, picking and choosing research programs and biotech startups to fund based on the founders' understanding of the science and favored goals. Amaranth has a strong focus on neuroscience, for example. The Amaranth pitch on the importance of focusing on bottlenecks in the research and development process is a more general call to action, however, and an interesting take on how best philanthropic organizations should direct their efforts in order to speed up the advent of human rejuvenation.

By 2029, the United States will spend $3 trillion dollars every year - half its federal budget - on adults aged 65 and older. By the same year, nearly 20 million Americans will die from age-related illnesses. Yet research on the biology of aging remains overlooked. Despite a 70-fold increase in funding for aging research since the last decade, the incentives of governments and for-profit investment do not always lend themselves to early bets on ambitious science or field-building. Amaranth is committed to filling this gap by funding moonshot approaches to longevity while expanding the field's talent pool.

In 2022, the Amaranth Advisory Board - a group of leading experts in longevity and neuroscience - convened to address the bottlenecks hindering progress in extending healthy human lifespan. During the meeting, the group enumerated focus areas that require philanthropic investment. Over the last two years (2021-2023), we've directed over $30M of funding to scientific labs, policy-makers, educational initiatives, and prize funding to further the most promising research in these overlooked areas.

Here, we outline initiatives which, if executed, could meaningfully accelerate the advancement of aging science and other life-extending technologies. The resulting document is a philanthropic menu, for which Amaranth is seeking both talent to execute on and co-funders.

Link: https://amaranth.foundation/bottlenecks-of-aging

The correlation between being overweight and risk of developing Alzheimer's disease is nowhere near as strong as, say, between being overweight and risk of developing type 2 diabetes. Given the evidence for chronic inflammation to be important in the development of Alzheimer's disease, and the many ways in which excess visceral fat tissue promotes chronic inflammation, it is somewhat puzzling that Alzheimer's isn't more of a lifestyle disease, similar to the way in which type 2 diabetes derives from lifestyle choices. That said, there is a contribution to Alzheimer's risk, and carrying excess weight is unwise, for this and many other reasons.

To try and identify Alzheimer's risks earlier, researchers assessed the association between brain MRI volumes, as well as amyloid and tau uptake on positron emission tomography (PET) scans, with body mass index (BMI), obesity, insulin resistance, and abdominal adipose (fatty) tissue in a cognitively normal midlife population. Amyloid and tau are proteins thought to interfere with the communication between brain cells. "Even though there have been other studies linking BMI with brain atrophy or even a higher dementia risk, no prior study has linked a specific type of fat to the actual Alzheimer's disease protein in cognitively normal people. Similar studies have not investigated the differential role of visceral and subcutaneous fat, especially in terms of Alzheimer's amyloid pathology, as early as midlife."

For this cross-sectional study, researchers analyzed data from 54 cognitively healthy participants, ranging in age from 40 to 60 years old, with an average BMI of 32. The participants underwent glucose and insulin measurements, as well as glucose tolerance tests. The volume of subcutaneous fat (fat under the skin) and visceral fat were measured using abdominal MRI. Brain MRI measured the cortical thickness of brain regions that are affected in Alzheimer's disease. PET was used to examine disease pathology in a subset of 32 participants, focusing on amyloid plaques and tau tangles that accumulate in Alzheimer's disease.

The researchers found that a higher visceral to subcutaneous fat ratio was associated with higher amyloid PET tracer uptake in the precuneus cortex, the region known to be affected early by amyloid pathology in Alzheimer's disease. This relationship was worse in men than in women. The researchers also found that higher visceral fat measurements are related to an increased burden of inflammation in the brain. "Several pathways are suggested to play a role. Inflammatory secretions of visceral fat - as opposed to potentially protective effects of subcutaneous fat - may lead to inflammation in the brain, one of the main mechanisms contributing to Alzheimer's disease."

Link: https://www.eurekalert.org/news-releases/1007871

A sizable fraction of research aimed at treating aging involves screening natural compounds in search of those that can modestly slow aging in short-lived animal models. This is because the economics of developing such a compound into a drug or supplement are well understood by investors, and because it dovetails well with the scientific goal of increased understanding of how aging progresses at the level of cellular biochemistry, rather than because it is going to make a big difference for patients. If sizable gains in healthy life span were the driving incentive, the field would look very different, and the emphasis would be on different approaches.

Today's publicity materials are a good example of the way in which unbiased screening works. It tends to find ways to influence the well-known set of mechanisms related to the calorie restriction response, responsible for the plasticity of life span in short-lived species. These include upregulation of autophagy, specific upregulation of mitophagy, the autophagic processes responsible for clearing damaged and worn mitochondria, improvement of mitochondrial function via other means, and so forth. The problem with adopting this approach is that calorie restriction and related alterations in metabolism produce much smaller gains in life expectancy in long-lived species than in the short-lived species used in screening. Thus unbiased screening as a basis for a program is more or less a guarantee of producing marginal therapies. We have to do better than this.

New drug-like molecule extends lifespan, ameliorates pathology in worms and boosts function in mammalian muscle cells

Defective mitophagy is implicated in many age-related diseases. It's tied to neurodegenerative disorders such as Parkinson's and Alzheimer's; it plays a role in cardiovascular diseases including heart failure; it influences metabolic disorders including obesity and type 2 diabetes; it is implicated in muscle wasting and sarcopenia and has a complex relationship with cancer progression. Even though interventions that restore mitophagy and facilitate the elimination of damaged mitochondria hold great promise for addressing these conditions, not one treatment has been approved for human use despite advances in the field.

MIC (Mitophagy-Inducing Compound) is a coumarin, which are naturally bioactive compounds that have anticoagulant, antibacterial, antifungal, antiviral, anticancer, and antihyperglycemic properties (among others) as well as being an antioxidant with neuroprotective effects. Coumarin is found in many plants and is found in high concentrations in certain types of cinnamon, which is one of the most frequent sources for human exposure to the substance. "We started screening natural compounds in neuronal cells and MIC came up as a major hit. Rather than taking MIC immediately into a mouse model we wanted to understand its impact on overall aging and identify its mechanism of action, so we took the work into the worm where we found that MIC is in a different class of molecules that enhance the expression of a key protein, TFEB."

Researchers found that MIC enhanced the activity of transcription factor TFEB, which is a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is the intracellular recycling process whereby cells clean up damaged proteins; it derives its abilities from the lysosome. Researchers found that MIC robustly increased the lifespan of C. elegans while also preventing mitochondrial dysfunction in mammalian cells.

Mechanistically MIC works upstream of TFEB by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12 (in worms)/FXR (in humans), which in turn induces mitophagy and extends lifespan. FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, where it acts to regulate levels of TFEB as part of a feed-fast cycle, but recently TFEB was shown to also be present in brain neurons. FXR is regulated by bile salts which are formed in the gut microbiome. "The gut microbiome impacts the body's use of bile acids. Aging impacts our microbiome. If levels of bile acids aren't correct it hinders mitophagy. That's how FXR can impact neuronal health. Neurons have a lot of mitochondria which makes mitophagy important in terms of neurodegeneration."

Parkinson's disease arises from the spread of misfolded α-synuclein proteins in the nervous system. This produces a wide array of dysfunction, but the most vulnerable cell population to this particular form of neurodegenerative pathology are domaminergenic cells. Their loss provokes the most evident symptoms of the condition. As noted here, this vulnerability appears to have something to do with clearance of damaged mitochondria, and thus with mitochondrial function more generally. Researchers are investigating ways to improve the situation, such as this representative small molecule approach.

Parkinson's disease is a neurodegenerative disorder caused by the progressive loss of the group of brain cells responsible for producing dopamine, a neurotransmitter that plays a critical role in regulating movement and coordination. As these neurons degenerate and dopamine levels decrease, individuals with Parkinson's disease experience a wide range of symptoms, including tremors, stiffness, and difficulties with balance and coordination.

Evidence suggests the dopamine-producing cells die off in Parkinson's disease because something has gone awry with the clearance of the cells' old and dysfunctional mitochondria - organelles that are the source of cells' energy, sometimes called the powerhouse of the cell. Researchers focused on an enzyme called USP30 which plays a role in this process. In a mouse model engineered to lack the gene that produces the enzyme - known as a "knockout model" because one specific gene has been deleted for the purposes of experimentation - the researchers observed that the loss of USP30 protected against the development of Parkinson's-like motor symptoms, increased clearance of damaged mitochondria in neurons, and protected against the loss of dopamine-producing neurons.

In a second set of experiments, the team validated the knockout studies using a proprietary molecule developed by Mission Therapeutics to block the enzyme's action in the dopamine-producing neurons. As in the knockout mice, inhibiting the enzyme's action increased clearance of dysfunctional mitochondria and protected dopamine-producing neurons.

Link: https://www.bidmc.org/about-bidmc/news/2023/11/researchers-halt-progression-in-parkinsons-disease-mouse-model

In that part of the tissue engineering community concerned with trying to reproduce natural skin structure, as best as possible with present technology, bioprinting is currently largely used for research and development rather than directly in clinical application as a regenerative therapy. For example, skin models are used in the screening and testing of topical therapies, and greater fidelity with natural skin gives more relevant information. Skin is a complex structure, in which cells associated with sweat glands and hair follicles appear to be important in coordinating growth and healing. The work noted here is an example of the state of the art in bioprinted skin; it remains to be seen as to the timeline for widespread use in the clinic.

Human skin comprises three major compartments, the hypodermis, the dermis, and the epidermis, each representing a rich cellular and biomolecular diversity. The skin also contains adnexal structures, such as the pilosebaceous unit, which is formed by the hair follicle and sebaceous gland. The pilosebaceous unit is further connected to the sweat apocrine gland, the arrector pili muscle, the underlying vasculature and is in contact with nerve cells. This complex structure is formed by about 15 types of cells distributed in concentric layers of cells of epithelial and mesenchymal origins.

Through life, different skin stem cell populations support the cyclic regeneration of the hair follicle and sebaceous gland. At the base of the hair follicle unit, the dermal papilla region is populated by cells known as dermal papilla cells (DPCs). These cells have a stem cell-like profile that allows the continuous and cyclic regeneration of the hair follicles. This characteristic is also part of the reason why the hair follicle units continue producing fibers in vitro. Furthermore, besides being an important route of chemical penetration into the skin, the pilosebaceous unit plays a crucial role in wound healing by providing cells that migrate into the damaged area and differentiate into the specific epidermal cells, demonstrating the relevance of this structure in skin tissue models for both permeation studies and in regenerative medicine as grafts.

Current approaches fail to adequately introduce complex adnexal structures such as hair follicles within tissue engineered models of skin. Here, we report on the use of 3D bioprinting to incorporate these structures in engineered skin tissues. Spheroids, induced by printing dermal papilla cells (DPCs) and human umbilical vein cells (HUVECs), were precisely printed within a pregelled dermal layer containing fibroblasts. The resulting tissue developed hair follicle-like structures upon maturation, supported by migration of keratinocytes and melanocytes, and their morphology and composition grossly mimicked that of the native skin tissue. Reconstructed skin models with increased complexity that better mimic native adnexal structures can have a substantial impact on regenerative medicine as grafts and efficacy models to test the safety of chemical compounds.

Link: https://doi.org/10.1126/sciadv.adg0297

The longest lived mice are still those engineered to lack functional growth hormone or growth hormone receptor. That record was established more than 20 years ago, and remains in place even as an energetic research and development community focused on treating aging as a medical condition has come into being. In part this is the case because research has largely focused on approaches known to produce lesser effects on aging in mice, such as the discovery of small molecules that mimic portions of the calorie restriction response. In part it is because the pace of development in the life sciences is ever slower than we would like it to be.

There are human practitioners of calorie restriction, and clinical trials have been conducted. This is how we know that calorie restriction in mice, largely operating through upregulation of autophagy, produces much larger effects on life span than is the case in humans. In the same way, there are humans who lack functional growth hormone or growth hormone receptor, the largest population of which exhibit Laron syndrome. Preliminary studies suggest that Laron syndrome provides some protection against cancer and metabolic disease, but there is no indication of extended life spans. So again the effect is small in humans in comparison to large in mice.

The consensus view on why this is the case is that humans are already fairly optimized for longevity, at least within the mammalian paradigm for cell and tissue biochemistry, or the parts of it most affected by calorie restriction and growth hormone metabolism. Our evolutionary history has been one in which we departed from our fellow primates in intelligence and sociology, leading to selection pressure for longer lives due to the ability of elders to help their descendants achieve reproductive success. Still, what about the rest of our biology? One of the most interesting questions in the field of aging research is how therapies to slow or reverse aging will differ in their performance between mice and humans once we depart from manipulation of growth-related metabolism to instead target the causes of aging, such as via clearance of senescent cells.

Insulin-like growth factors and aging: lessons from Laron syndrome

Pituitary-derived growth hormone (GH) along with insulin-like growth factor-1 (IGF1) constitute an endocrine axis with critical roles in growth and development. IGF1 is evolutionarily and structurally related to insulin. IGF1 production continues to be dependent on hypophysial GH secretion throughout all stages of life. Aging is linked to various endocrine deficits. In the specific context of the somatotrophic axis, GH and IGF1 biosynthesis progressively decrease as we age due to reduced activity of the hypothalamic GH releasing hormone (GHRH)-GH neuroendocrine system. Thus, while maximal GH and IGF1 levels are reached at mid-puberty, concentrations around the eight decade of life become drastically reduced. Indeed, both the amplitude of the GH secretory pulses as well as the basal levels between pulses are largely decreased. Reduction of endocrine GH levels is closely followed by a parallel decline in circulating IGF1.

Evidence has accumulated in recent years demonstrating that disturbance of the GH-IGF1 network correlates with prolonged lifespan in a number of animal species, including flies (D. melanogaster), nematodes (C. elegans) and mouse (M. musculus). Male mice harboring a disrupted GH receptor (GHR) gene ('Laron' mice) survive 55% longer than wild-type animals whereas female Laron mice have a 38% longer lifespan. The cellular and biochemical mechanisms that are responsible for the association between abrogation of the GH-IGF1 axis and prolonged lifespan are complex. Briefly, these mechanisms are functionally linked to the physiological role played by these hormones in nutrient sensing. Of relevance, whereas the effect of individual mutations on lifespan and health span in humans is usually difficult to assess, genomic analyses identified several differentially-represented aging-associated genes in Laron syndrome (LS) patients.

Epidemiological analyses have shown that patients with LS, the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms.

One can measure aging from the bottom up, looking at the most fundamental changes in cell and tissue biochemistry, or one can measure aging from the top down, looking at decline in specific high-level capabilities of the individual. For the two approaches to meet in the middle remains a distant prospect for even simple tissues, never mind the most complex organs, such as the brain. Therapies to reverse aging will be a going concern long before aging is completely mapped, top to bottom. As an example of starting at the top, in a very conceptual way, one might look at the paper here, and its view of one specific aspect of cognitive aging.

Many new technologies, such as smartphones, computers, or public-access systems (like ticket-vending machines), are a challenge for older adults. One feature that these technologies have in common is that they involve underlying, partially observable, structures (state spaces) that determine the actions that are necessary to reach a certain goal (e.g., to move from one menu to another, to change a function, or to activate a new service).

In this work we provide a theoretical, neurocomputational account to explain these behavioral difficulties in older adults. Based on recent findings from age-comparative computational- and cognitive-neuroscience studies, we propose that age-related impairments in complex goal-directed behavior result from an underlying deficit in the representation of state spaces of cognitive tasks. Furthermore, we suggest that these age-related deficits in adaptive decision-making are due to impoverished neural representations in the orbitofrontal cortex and hippocampus.

Link: https://doi.org/10.1177/17456916231204811

Study of the biochemistry of the human brain is hindered by the difficulty of accessing tissue samples. Most work is conducted on post-mortem tissue rather than samples taken from a living brain (such as during surgery), and few research groups have the necessary connections to obtain these materials. Thus the development of brain organoids is important in this part of the medical research field, even given that most present organoid recipes result in a poor substitute for actual tissue. Here, researchers use post-mortem tissue and organoids to demonstrate that senescent cells are important in the aging of the brain, and in the effects of COVID-19. This is one of many data points to suggest that treatment with senolytics capable of passing the blood-brain barrier (such as the dasatinib and quercetin combination) will be beneficial in older individuals.

Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks. In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature.

Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression. Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments.

Link: https://doi.org/10.1038/s43587-023-00519-6

Recent years have made it clear that any sufficiently large set of data derived from biochemistry or physiology can be fed into a machine learning process to develop an weighted combination of measures that reflects biological age. These aging clocks have been derived from many forms of omics data, from frequently measured blood biomarkers, from various other combination of common measures of health. Interestingly, photography of the face and, separately, of retinal structure also provide enough data for the development of clocks. In today's open access paper, researchers report on a clock developed from photography of the lens of the eye.

All of these clocks are discovered, not designed. Thus once a given weighted combination of measures is in hand, the next, harder question is how exactly it relates to the underlying processes of aging. This is important because we want clocks that work well to assess the effects of novel interventions and potential interventions on the state of biological age. It we can't be certain that a clock will, say, accurately reflect the contribution of senescent cells to aging, then one can't trust that clock in testing the effects of senolytic therapies that clear senescent cells. One would have to calibrate the clocks against the therapy in life span studies, which somewhat defeats the point of having a clock in the first place. The development of sufficient data and understanding to circumvent this issue is the primary challenge in the ongoing development of aging clocks.

LensAge index as a deep learning-based biological age for self-monitoring the risks of age-related diseases and mortality

Assessing an individual's aging process is important to evaluate one's health status. As one ages, the human body becomes frail with regard to biological functions and the occurrence of chronic diseases, such as Alzheimer's disease, cancer, diabetes, and cardiovascular diseases. Chronological age is defined as the time that an individual has experienced since birth. Since aging involves complex determinants, including genetic regulation, and the nutritional and environmental factors, peers with the same chronological age vary in aging and may have different health status and life expectancy. Thus, chronological age does not precisely reveal the true physiological age of individuals.

Biological age assessment based on various physiological biomarkers can quantitatively evaluate the degree of aging and predict the mortality and incidence of age-related diseases more accurately than chronological age. However, measuring biological age is challenging, largely due to obstacles in sample collection, variable aging rates of different tissues, and insufficient reliability of measuring tools and protocols. Intensive investigations of the biological indicators reflecting the overall aging pace of the human body are currently underway. For example, invasive methods measuring telomere length and DNA methylation status, profiling transcriptomics and proteomics, and the inflammatory aging clock have been used to generate biomarkers of aging at the molecular level using human blood cells. Furthermore, noninvasive techniques using machine learning and medical imaging, such as chest X-ray, magnetic resonance imaging (MRI) of the brain, and 3D facial imaging, were introduced to evaluate biological aging. However, these techniques are limited by high costs or instability in clinical practice. Therefore, a more objective, reliable, convenient, and noninvasive method that can accurately evaluate the biological age of an individual has yet to be developed for broader applications and self-management of health status.

The human lens, located in the anterior segment of the eye, is transparent under normal conditions and exchanges substances with the vitreous through the aqueous humor cycle. Age-dependent changes in the lens include nucleus enlargement, elasticity reduction, and increased opacity, all of which can be objectively and reliably observed through noninvasive imaging and rapidly assessed using digital photography. Thus, the human lens appears to be an optimal tissue with unique advantages for assessing biological age.

In this study, we used informative lens photographs to generate LensAge as an innovative indicator to reveal aging status of lens based on deep learning (DL) models. Under ideal physiological conditions (both genetic and environmental), biological age should be synchronized with chronological age. While in reality, there are almost always differences between biological age and chronological age, which is considered to result from individually different aging processes. Therefore, we measured the difference between LensAge and chronological age as the LensAge index to assess an individual's aging rate relative to peers, and investigated its ability to evaluate the risks of age-related disease occurrence and all-cause mortality. Importantly, we tested whether our models can be generalized to smartphone-based lens photographs, which may have potential applications for self-monitoring the risks of age-related diseases and mortality during aging.

The work on pentadecanoic acid noted here is interesting, but should be taken with a grain of salt given that it is performed in vitro. In general, one should expect any given set of mechanisms in the cell to be associated with many different means of manipulation. It is interesting to see a fatty acid capable of touching on the same mechanisms as rapamycin, but remember that the ability to influence the same mechanistic targets does not necessarily translate to the same ability to produce a modest slowing of aging in animal studies. So the usual advice stands here, to wait for the animal studies before getting too excited.

The BioMAP Diversity PLUS system includes a series of independently run and industry-standard pharmacological assays routinely used to screen and compare molecules for activity profiles and clinical indications as well as safety. Specifically, the BioMAP Diversity PLUS system tests molecules across 12 primary human cell-based systems mimicking various disease states and measures the molecule's effects across 148 clinically relevant biomarkers at four doses. The resulting cell-based phenotypic profile enables valuable insights into potential clinical applications of a compound, as well as identifying shared key activities with other compounds of interest.

Pentadecanoic acid (C15:0), an odd-chain saturated fatty acid, has mounting evidence of being essential to supporting cardiometabolic and liver health. People with low circulating C15:0 concentrations have a higher risk of having or developing type 2 diabetes, heart disease, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis, as well as specific types of cancer. As an essential fatty acid, C15:0 should, by definition, support healthspan, and longevity. Further, C15:0 has mTOR-inhibiting and AMPK-activating activities shared with rapamycin and metformin, respectively. As such, we compared the primary human cell phenotypic profile of C15:0 with acarbose, metformin, and rapamycin using BioMAP Diversity PLUS to objectively evaluate common clinically relevant cell-based activities supportive of an expanded healthspan and lifespan. Based on our findings, we then reviewed the literature for further evidence of C15:0 as a longevity-enhancing nutrient.

At their optimal doses, C15:0 (17 µM) and rapamycin (9 µM) shared 24 activities across 10 cell systems, including anti-inflammatory (e.g., lowered MCP-1, TNFα, IL-10, IL-17A/F), antifibrotic, and anticancer activities, which are further supported by previously published in vitro and in vivo studies. Paired with prior demonstrated abilities for C15:0 to target longevity pathways, hallmarks of aging, aging rate biomarkers, and core components of type 2 diabetes, heart disease, cancer, and nonalcoholic fatty liver disease, our results support C15:0 as an essential nutrient with activities equivalent to, or surpassing, leading longevity-enhancing candidate compounds.

Link: https://doi.org/10.3390/nu15214607

Some interesting numbers for the effects of weight loss in obese individuals on risk of age-related disease arise from the use of semaglutide in clinical trials. In the study noted here, treated individuals lost 9% of body weight versus 1% for the placebo arm. The outcome of that is at least as good as the use of statins when it comes to effects on cardiovascular disease. The lesson to take away from this is likely that being overweight is more harmful than most people like to think that it is. Existing data is certainly supportive of that conclusion. Excess visceral fat tissue has been shown to lead to a shorter life expectancy, higher lifetime medical costs, greater incidence of all common age-related disease, and the more of it, the worse the outcome.

In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.

A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean duration of exposure to semaglutide or placebo was 34.2 ± 13.7 months, and the mean duration of follow-up was 39.8 ± 9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group.

Link: https://doi.org/10.1056/NEJMoa2307563

The raised blood pressure of hypertension causes a great deal of downstream damage. It is a way for low-level biochemical damage associated with aging to become actual physical damage to the body. Pressure damage can occur in delicate tissues throughout the body, and raised blood pressure increases the pace at which capillaries and other small vessels rupture. Further, increased blood pressure can accelerate the development of atherosclerosis, and also contributes to the pathological enlargement and weakening of heart muscle. All of this downstream harm is why forcing a reduction in blood pressure, without addressing any of the underlying cell and tissue damage that causes hypertension, can nonetheless produce benefits to long-term health. Antihypertensive medications do not in any way touch upon the biochemistry of aging, but rather act to force regulatory mechanisms of blood pressure into a certain state.

There is a great deal of epidemiological evidence to show that higher blood pressure correlates with increased mortality and risk dementia. There is also a good deal of evidence for control of blood pressure via hypertensive drugs to reduce mortality and risk of dementia. Today's notes on recent research add to this evidence, reporting on a recent study in China. In this context, it is worth noting that in recent years it has become clear that lower blood pressure is better even in the normal range, that reducing below the 120s mmHg systolic blood pressure that are the present target continues to produce benefits.

Lowering blood pressure significantly reduced dementia risk in people with hypertension

Researchers evaluated the effectiveness of lowering blood pressure on dementia risk among people with high blood pressure. The study was conducted in 326 villages in rural China and included approximately 34,000 adults, ages 40 and older, with untreated blood pressure of 140/90 mm Hg or higher, or 130/80 mm Hg or higher for people at high risk for cardiovascular disease or those currently taking blood pressure medication. Half of the villages were randomly assigned to a village doctor-led intensive blood pressure intervention strategy, and half of the villages were randomly assigned to usual care. Patients in the usual care villages received their hypertension management from local village doctors or primary care physicians at township hospitals as part of routine health service covered by the China New Rural Cooperative Medical Scheme (a health insurance plan covering approximately 99% of rural residents for basic health-care services in China).

In the intervention group, trained village doctors initiated and adjusted antihypertensive medications based on a straightforward treatment protocol to achieve a goal of lowering systolic blood pressure to less than 130 mm Hg and diastolic blood pressure to less than 80 mm Hg, with supervision from primary care physicians. The stepwise protocol for hypertension management included a treatment algorithm, selection of medication, review of contraindications of medications and, finally, strategies to adjust dose. They also provided discounted and free blood pressure medications to patients and conducted health coaching on lifestyle modifications, home blood-pressure measurement and medication adherence.

The analysis found that the people in the intervention group showed significant improvement in blood pressure control and reduced dementia and cognitive impairment, no dementia compared to those who received usual care. The average blood pressure in the intervention group at 48 months was 128/73 mm Hg, compared to 148/81 mm Hg in the usual care group. On average, systolic blood pressure decreased by 22 mm Hg and diastolic blood pressure decreased by 9 mm Hg among people in the intervention group compared to usual care. People in the intervention group had 15% lower risk of dementia and 16% lower risk of memory impairment compared to the group that received usual care. Serious adverse events, such as hospitalizations and death from all causes, were also less frequent in the intervention group.

The research and development community is ever in search of the next statin drug, and a way to reduce lipoprotein(a) levels looks very much like an alternative statin. Statins reduce the amount of cholesterol carried by LDL particles in the bloodstream. Lipoprotein(a) is a carrier of cholesterol, like LDL, and research has shown that high levels correlate with the development of atherosclerotic lesions, as is the case for LDL-cholesterol. That being so, one can't be all that optimistic that a treatment to reduce lipoprotein(a) will actually do much for disease risk. Statins reduce risk of stroke and heart attack resulting from atherosclerosis by, at most, and arguably, 20% or so - levels of cholesterol carried in the bloodstream are not the most important input to the disease process. A quarter of humanity still dies from these conditions in the environment in which everyone who can take statins is taking statins. Statins continue to make a great deal of profit for pharmaceutical companies, however, so developing something that looks very much like a statin? That sounds great to the powers that be.

Findings from a phase 1 trial show that a single dose of an experimental therapy, lepodisiran, produced greater than 94% reductions in blood levels of lipoprotein(a), a key driver of heart disease risk, with the results lasting for nearly a year. Lipoprotein(a), often shortened to just Lp(a), is made in the liver and has similarities to LDL, also known as low-density lipoprotein or "bad cholesterol." Unlike other types of cholesterol particles, Lp(a) levels are 80-90% genetically determined. The structure of the Lp(a) particle causes the accumulation of plaque in arteries which greatly increases the risk of heart attacks and strokes.

Although effective therapies exist to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, currently there are no approved drug treatments to lower Lp(a). Since Lp(a) levels are determined by a person's genes, lifestyle changes (diet or exercise) have no effect. In the trial, participants who received an injection of lepodisiran had lipoprotein(a) levels reduced by the top dose as much as 96% within two weeks and maintained levels more than 94% below baseline for 48 weeks. The drug is a small interfering RNA (siRNA) therapeutic that blocks the messenger RNA needed to manufacture a key component of lipoprotein(a) in the liver.

Link: https://www.eurekalert.org/news-releases/1007716

The presence of senescent cells can make a tissue environment more hospitable for cancer, as senescent cells secrete growth factors in addition to pro-inflammatory signals. Researchers have provided evidence for some cancers to aggressively employ the strategy of inducing senescence. Here, a research group notes that this induction of senescence can act to suppress the local immune response to a cancer by co-opting immune cells, making them senescent. It remains an open question as to whether targeting senescent cells for destruction is a good idea in the early stages of a cancer, rather than leaving them in place to attract the immune system to the tumor, but this work suggest that it will be useful, acting to remove pro-cancer signaling.

Cancerous tumors consist of a mixture of cells, the most important of which are cancer stem cells. These cells are capable of establishing new cancerous tumors by evading the immune response. Researchers examined the mechanisms by which cancer stem cells evade immune response in mice models. They showed that cancer stem cells induce senescence in macrophages - the immune cells which are responsible for the first step of the destruction of cancer cells.

The team used two cell lines of glioblastoma tumor, one of which was capable of inducing tumor formation (cancer stem cell) and the other of which was not. In mice models, the cancer stem cells suppressed the proliferation of macrophages; further investigation showed that macrophages cultured with cancer stem cells exhibit senescence or cellular aging. Macrophages were not the only immune cells affected; while the proliferation of T cells was unchanged, their antitumor activity was suppressed due to the immunosuppressive factors produced by senescent macrophages. The team identified interleukin 6 (IL-6) produced by cancer stem cells as the molecule responsible for triggering these effects.

The team also demonstrated that supplementing the mice inoculated with cancer stem cells with a molecule called nicotinamide mononucleotide resulted in the proliferation of non-senescent macrophages and reduced the immunosuppressive factors produced by senescent macrophages, preventing tumor growth and leading to increased survival times in mice. Future work will focus on two avenues: confirming that this discovery holds true for cancers other than glioblastomas, and confirming that the findings apply to cancers in humans.

Link: https://www.global.hokudai.ac.jp/blog/cancer-stem-cells-trigger-macrophage-aging/

When it comes to treating aging as a medical condition, it is important to fund the right sort of research program. All too much of the field of translational aging research is focused on finding ways to produce small benefits, such as via the use of repurposed existing supplements. This may produce gains for investors, but it won't meaningfully change the present shape of a human life. We need to do better than that. Fortunately, there are a small number of non-profit organizations and academic groups focused on development of the means of rejuvenation, rather than on means of modestly slowing aging. Two of the best are the SENS Research Foundation and LEV Foundation, both informed by the Strategies for Engineered Negligible Senescence (SENS), a list of important contributing causes of aging, the cell and tissue damage that causes dysfunction, alongside proposed forms of therapy to repair that damage.

Both of these non-profit organizations are presently running year end fundraisers to support their ongoing research programs, covering important areas of aging and rejuvenation that are not receiving sufficient attention elsewhere in the research community, or that are slowed by challenges in the fundamental science, or that are neglected by researchers due to a lack of tooling or a foundation to proceed. I consider both the SENS Research Foundation and LEV Foundation to be worthy recipients for your charitable donations. If you want to see a future in which aging has become a treatable medical condition, then take action! Do something to help the groups that are trying to make that future a reality! Funding makes the world turn; progress in building the foundations for rejuvenation therapies depends upon those funds.

SENS Research Foundation: Welcome to our 2023 End of Year Campaign

SENS Research Foundation (SRF) has spent the past year diligently employing your generous contributions towards accelerating the development of therapies to prevent, treat, and cure the diseases of aging. Just this year we've spoken at longevity conferences, highlighted our work with US policy makers and global leaders in health, submitted patents and publications on our research, educated dozens of students, supported translational therapies in their journey to market, and so much more. This End of Year Campaign focuses on SRF and the relationships we have built over the last couple years. These collaborations grow the effectiveness of our community and industry, extending our reach and deepening our impact to target directly the diseases and disabilities of aging. Every week we highlight a new organization and the real-world impact they are making to turn our mission into reality.

LEV Foundation: 2023 End-of-Year Fundraiser

LEV Foundation's story has just begun. In 2024, with your support, we're planning to: (a) Initiate the second study in the Robust Mouse Rejuvenation program. Building on the success of the ongoing first experiment, RMR-2 will shed light on the interactions between a new panel of therapies. (b) Bring the Dublin Longevity Declaration's message of hope to a global audience, through a major media campaign including translations into most widely-spoken languages. We'll recruit more renowned signatories - and even more importantly, build on the foundation the Declaration has provided to engage with policymakers and leaders around the world, seeking concrete action on its fundamental recommendation: to immediately expand research on extending healthy human lifespans. (c) Organize and support the next Longevity Summit Dublin, scheduled to take place on June 13-16, 2024. Speakers will be announced over the coming months, but we're already very confident that the third edition of the Summit will be just as unmissable as the first two events. (d) Continue enabling our partners at the Healthspan Action Coalition, Alliance for Longevity Initiatives (A4LI), and AfroLongevity, to build stronger connections with established public- and private-sector organizations, enhancing awareness of the potential of longevity research amongst those who set priorities for healthcare and research funding at all levels. A4LI's goals for the coming year include establishing an annual legislative briefing for longevity science in the US House of Representatives, and promoting passage of the Advanced Approval Pathway for Longevity Medicines.

Axons are lengthy projections of the cell body that connect neurons, essential to the function of the brain. Researchers here view what is known of the biochemistry of Alzheimer's disease through the lens of damage to axons. As they point out, the relentless focus on protein aggregation, particularly amyloid-β aggregation, in Alzheimer's disease does tend to crowd out more in-depth discussions of what it is that this protein aggregation actually does to cells.

Alzheimer's disease (AD) is the primary cause of dementia and is anticipated to impose a substantial economic burden in the future. Over a significant period, the widely accepted amyloid cascade hypothesis has guided research efforts, and the recent FDA approval of an anti-amyloid-β antibody, believed to decelerate AD progression, has further solidified its significance. However, the excessive emphasis placed on the amyloid cascade hypothesis has overshadowed the physiological nature of Aβ and tau proteins within axons.

Axons, specialized neuronal structures, sustain damage during the early stages of AD, exerting a pivotal influence on disease progression. In this review, we present a comprehensive summary of the relationship between axonal damage and AD pathology, amalgamating the physiological roles of amyloid-β and tau proteins, along with the impact of AD risk genes such as APOE and TREM2. Furthermore, we underscore the exceptional significance of axonal damage in the context of AD.

Link: https://doi.org/10.3389/fnagi.2023.1264448

The ability of the body to build new blood vessels declines with age. One of the consequences is a loss of capillary density in tissues throughout the body, reducing the supply of nutrients and contributing to harmful changes in the fluid dynamics of the vasculature. Researchers have shown that increasing the ability to build and maintain capillaries via upregulation of VEGF can extend life in mice. Here, researchers report on another approach to increasing the capacity for vascularization in mice. The goal of increasing capillary density is an important one, but few research groups or companies are focused on this in any meaningful way.

The stem cell theory of aging dictates that a decline in the number and/or function of stem cells causes tissue degeneration and aging; however, it still lacks unequivocal experimental support. Here, using lineage tracing and single-cell transcriptomics, we identify a population of CD133+ bone marrow-derived endothelial-like cells (ELCs) as potential endothelial progenitor cells, which contribute to tubular structures in vitro and neovascularization in vivo. We demonstrate that supplementation with wild-type and young ELCs respectively restores neovascularization and extends lifespan in progeric and naturally aged mice.

Mechanistically, we identify an upregulation of farnesyl diphosphate synthase (FDPS) in aged CD133+ ELCs-a key enzyme in isoprenoid biosynthesis. Overexpression of FDPS compromises the neovascularization capacity of CD133+ ELCs, whereas FDPS inhibition by pamidronate enhances neovascularization, improves health measures and extends lifespan in aged mice. These findings highlight stem cell-based strategies for the treatment of progeria and age-related pathologies.

Link: https://doi.org/10.1038/s43587-023-00512-z

Here find an interesting commentary on some of the evolved genetic differences between mammals and birds, with a focus on genes relevant to energy metabolism - and potentially to species longevity. Larger animals live longer, but birds tend to be long-lived for their size. This is also the case for some bat species. It is thought that adaptations to energy metabolism needed to support the very energy-intensive activity of flight are involved in this increased longevity, providing resilience as a side effect.

The details have yet to be mapped in any comprehensive way, but studies such as today's open access example are steps towards that goal. Energy metabolism is closely associated with mitochondrial function and oxidative stress, both of which appear strongly connected to processes of aging. Loss of mitochondrial function and rising oxidative stress are features of aging, but in the short term are also features of exertion. It is plausible to argue that systems that evolved to cope with and minimize the side effects of high energy expenditure seem likely to also increase longevity. It is perhaps interesting that this isn't universal, that we do still see comparatively short-lived birds and bats despite their capability of flight.

As with all such research, it is an open question as to whether there is anything to find that could form the basis for near-term therapies in humans. In the much longer term, rebuilding human biology from the ground up will certainly take place, incorporating everything learned from a study of comparative biology, and likely going beyond to the production of wholly artificial biological systems that are better yet, but those of us reading this now only have so much time on hand to await treatments capable of producing longer healthy life spans.

Gene purging and the evolution of Neoave metabolism and longevity

Aves emerged from bipedal dinosaurs ∼165-150 million years ago (MYA), survived the Cretaceous-Paleogene extinction event 66 MYA, and then diversified into the ∼10,000 Neoaves species we observed today. The benefits of becoming endothermic, smaller, and adapted for flapping-wing flight allowed for greater foraging opportunities, predator avoidance, and tolerance to a great range of environments. The power required to fly long distances is largely a multiple of basal metabolic rates (BMR), and smaller birds with proportionately more fat reserves can fly longer distances than large birds. Indeed, genes involved in energy metabolism show strong evidence of positive selection, suggesting early adaptative mutations required for flight. Body mass correlates with BMR and longevity, although shifts and variation across vertebrate phylogeny remain unexplained. Many Neoaves are outliers, showing greater longevity and higher BMR than expected relative to body size.

Maintenance of the proteasome requires oxidative phosphorylation to produce ATP and mitigation of oxidative damage, in an increasing dysfunctional relationship with aging. SLC3A2 plays a role on both sides of this dichotomy as an adaptor to SLC7A5, a transporter of branched-chain amino acids (BCAA), and to SLC7A11, a cystine importer supplying cysteine to the synthesis of the antioxidant glutathione. Endurance in mammalian muscle depends in part on oxidation of BCAA, however elevated serum levels are associated with insulin resistance and shortened lifespans. Intriguingly, the evolution of modern birds (Neoaves) has entailed the purging of genes including SLC3A2 and SLC7A5, largely removing BCAA exchangers in pursuit of improved energetics.

Additional gene purging included mitochondrial BCAA aminotransferase (BCAT2), pointing to reduced oxidation of BCAA and increased hepatic conversion to triglycerides and glucose. Fat deposits are anhydrous and highly reduced, maximizing the fuel/weight ratio for prolonged flight, but fat accumulation in muscle cells of aging humans contributes to inflammation, and senescence. Duplications of the bidirectional α-ketoacid transporters SLC16A3, SLC16A7, the cystine transporters SLC7A9, SLC7A11, and N-glycan branching enzymes MGAT4B, MGAT4C in Neoaves suggests a shift to the transport of deaminated essential amino acid, and stronger mitigation of oxidative stress supported by the galectin lattice.

The amyloid cascade hypothesis of Alzheimer's disease suggests that the disease arises from misfolding and aggregation of amyloid-β, which grows to disrupts brain metabolism to produce inflammation and tau aggregation in later stages of the condition. While the amyloid cascade hypothesis remains the dominant view of the causes of Alzheimer's disease, there are other views. For example, that persistent infection leads directly to a runaway feedback loop of chronic inflammation and tau aggregation. In this view, amyloid-β aggregation is a side-effect, given that amyloid-β appears to be an anti-microbial peptide, a part of the innate immune response that is expected to be present in greater amounts during a persistent infection. Here, researchers discuss the potential role of microbial colonization of the brain in Alzheimer's disease, while noting that the evidence remains much debated.

Controversies surrounding the validity of the toxic proteinopathy theory of Alzheimer's disease have led the scientific community to seek alternative theories in the pathogenesis of neurodegenerative disorders (ND). Recent studies have provided evidence of a microbiome in the central nervous system. Some have hypothesized that brain-inhabiting organisms induce chronic neuroinflammation, leading to the development of a spectrum of NDs. Bacteria such as Chlamydia pneumoniae, Helicobacter pylori, and Cutibacterium acnes have been found to inhabit the brains of ND patients. Furthermore, several fungi, including Candida and Malassezia species, have been identified in the central nervous system of these patients.

However, there remains several limitations to the brain microbiome hypothesis. Varying results across the literature, concerns regarding sample contamination, and the presence of exogenous DNA have led to doubts about the hypothesis. These results provide valuable insight into the pathogenesis of NDs. Herein, we provide a review of the evidence for and against the brain microbiome theory and describe the difficulties facing the hypothesis. Additionally, we define possible mechanisms of bacterial invasion of the brain and organism-related neurodegeneration in NDs and the potential therapeutic premises of this theory.

Link: https://doi.org/10.3389/fnagi.2023.1240945

There is a great deal of data on air quality for researchers to peruse and link to the even larger set of data on human health and mortality. This has resulted in studies demonstrating strong correlations between higher levels of particulate air pollution and raised mortality, both in the context of exposure differences between large regions, and in the variations across a single metropolitan area. A large part of the problem is smoke, with industry, wildfires, and cooking fires all contributing to this issue to different degrees in different regions. Mechanistically, these particles lead to increased chronic inflammation through their interactions with lung tissue, and raised chronic inflammation contributes to the onset and progression of all of the common fatal age-related conditions.

Aging is a complex biological process involving multiple interacting mechanisms and is being increasingly linked to environmental exposures such as wildfire smoke. In this review, we detail the hallmarks of aging, emphasizing the role of telomere attrition, cellular senescence, epigenetic alterations, proteostasis, genomic instability, and mitochondrial dysfunction, while also exploring integrative hallmarks - altered intercellular communication and stem cell exhaustion. Within each hallmark of aging, our review explores how environmental disasters like wildfires, and their resultant inhaled toxicants, interact with these aging mechanisms. The intersection between aging and environmental exposures, especially high-concentration insults from wildfires, remains under-studied.

Preliminary evidence, from our group and others, suggests that inhaled wildfire smoke can accelerate markers of neurological aging and reduce learning capabilities. This is likely mediated by the augmentation of circulatory factors that compromise vascular and blood-brain barrier integrity, induce chronic neuroinflammation, and promote age-associated proteinopathy-related outcomes. Moreover, wildfire smoke may induce a reduced metabolic, senescent cellular phenotype. Future interventions could potentially leverage combined anti-inflammatory and NAD+ boosting compounds to counter these effects. This review underscores the critical need to study the intricate interplay between environmental factors and the biological mechanisms of aging to pave the way for effective interventions.

Link: https://doi.org/10.3389/ftox.2023.1267667

Senescent cells accumulate throughout the body with age. They are created constantly due to stresses placed upon cells, and when somatic cells reach the Hayflick limit on replication, and are cleared by the immune system. This process of clearance slows down with age, unfortunately, and so a burden of lingering senescent cells begins to build up. Senescent cells are disruptive to tissue structure and function, even when present in comparatively small numbers relative to other cells in a tissue, as a result of the pro-growth, pro-inflammatory signals that they generate.

Atherosclerosis involves the generation of fatty lesions that narrow and weaken blood vessels, and is the leading cause of human mortality, as rupture of these lesions causes stroke and heart attack. We might view it as a condition of macrophage dysfunction, as these are the cells tasked with cleaning up the excess cholesterol and cell debris that form the bulk of an atherosclerotic lesion. The lesions grow to the degree that macrophages become overwhelmed and begin to die, calling for more support as they do so. In this context, to what degree is atherosclerosis driven by cellular senescence? And which sort of senescent cells?

It is known that cells become senescent in and around atherosclerotic lesions, and that clearing them in animal models helps to slow progression of pathology; one can speculate on the mechanisms by which various types of senescent cell can contribute to make the lesion environment worse. Sadly, no-one has yet run clinical trials of the known senolytic drugs capable of clearing senescent cells in human patients. Nor are they likely too, given the high costs of such a trial, and the inability to profit from new data on existing drugs.

New Dawn for Atherosclerosis: Vascular Endothelial Cell Senescence and Death

Atherosclerosis is a chronic cardiovascular disease (CVD) that poses significant risks to human health, and is the underlying cause of peripheral vascular disease, coronary heart disease, and stroke. The pathogenesis of atherosclerosis is complex and involves various cell types, including endothelial cells (ECs), vascular smooth muscle cells (SMCs), adventitial fibroblasts, macrophages, and other immune cells. Key factors in the development of atherosclerosis include endothelial dysfunction, leukocyte adhesion, foam macrophage formation, and SMC phenotypic transition.

Endothelial dysfunction is considered the initial step in atherosclerosis, and in its broadest sense, it encompasses a constellation of nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone, redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. ECs that line elastic arteries, such as the aorta, carotid artery, and femoral artery, have critical functions in maintaining vascular homeostasis. The primary function of the endothelium is to produce nitric oxide (NO) and other vasoactive substances to regulate vascular tone.

ECs form a continuous monolayer barrier that controls substance exchange among the lumen, vascular wall, and parenchyma. A specialized barrier function of the endothelium involves its immunoregulatory effects on leukocyte recruitment. Quiescent endothelium is immunosuppressive, with a surface glycoprotein profile that prevents leukocyte adhesion, crawling, and extravasation. Upon tissue injury and inflammatory stress, activated ECs present adhesive molecules, such as vascular cell adhesion molecule-1 (VCAM-1), to the cell surface to facilitate the transendothelial migration of leukocytes. The reactive, pro-inflammatory phenotype of ECs is indispensable for tissue repair after acute injury. However, in the context of chronic tissue damage, such as atherosclerosis, persistent endothelial inflammation becomes pathogenic. Moreover, the regenerative capacity of ECs is intrinsically critical to the re-endothelialization of the surface-eroded arterial lumen and the stabilization of atherosclerotic lesions. Notably, most of these endothelial dysfunctions are associated with endothelial cell senescence and death.

Cellular senescence is a process in which cells undergo permanent cell cycle arrest, with an altered secretome to remodel neighboring cells and the extracellular matrix (ECM) microenvironment. Notably, vascular aging in animal models and humans is characterized by impaired endothelium-dependent dilation (EDD), perturbed fibrinolysis, enhanced permeability, and aberrant angiogenesis. In humans, endothelium-dependent vasodilation, usually measured as flow-mediated dilation of the radial artery, serves as a non-invasive marker of vascular aging and cardiovascular damage, even in the absence of clinical symptoms. Importantly, cellular senescence of the endothelium is an integral component of vascular aging, as well as atherosclerosis. EC senescence triggers structural and functional deterioration of the vascular wall by not only deterring re-endothelialization and barrier reconstitution at the injury zone, but also promoting an inflammatory and thrombotic niche via the senescence secretome, thereby contributing to the development and progression of CVD.

In animal studies, icariin has been shown to favorably change the balance of microbial populations in the aging gut microbiome, and is modestly protective against a range of age-related declines. How exactly it operates remains to be seen, but given that it alters the gut microbiome, there are likely many relevant mechanisms that stem from the influence of the microbiome on cell function through the body. Researchers here note that icariin reduces a form of programmed cell death in the aged brain, a contributing cause of neurodegeneration.

Icariin (ICA) is a flavonoid compound. ICA has multifarious pharmacological effects such as anti-depression, improvement of ischemic brain injury, anti-dementia, and anti-aging. Research on Alzheimer's disease (AD) has found that ICA possesses certain effects, with diverse mechanisms. ICA can reduce amyloid-β deposition to improve the symptoms of AD animal models, and its mechanism of action may be associated with the regulation of PI3K/AKT. In the nervous system, ICA can antagonize the damaging effect of neurotoxins on neurons in the rat cortex and hippocampus, and its mechanisms may be achieved by inhibiting the activation of microglia cells, reducing the production of inflammatory cytokines, alleviating the damage of inflammatory transmitters to neurons, and improving the learning and memory abilities of mice.

In the research of AD, it has been found that ferroptosis of nerve cells is a major event of nerve injury, and glial cell death also plays an important regulatory role in AD. Apart from conventional oxidative stress regulation, P53 is one of the important proteins that induce ferroptosis. P53 and MDM2 combine into a complex to regulate SLC7A11C and mediate lipid peroxidation. In this study, we attempted to further explain the role, exact mechanism and target of ICA in treating AD from the ferroptosis perspective. We found that ICA could improve the neurobehavioral, memory, and motor abilities of AD mice. It could lower the ferroptosis level and enhance the resistance to oxidative stress. After inhibition of MDM2, ICA could no longer improve the cognitive ability of AD mice, nor could it further inhibit ferroptosis. Network pharmacological analysis revealed that MDM2 might be the target of ICA action.

Link: https://doi.org/10.18632/aging.205144

The amyloid cascade hypothesis of Alzheimer's disease suggests that aggregation of misfolded amyloid-β sets the stage for a feedback loop between chronic inflammation of brain tissue and tau aggregation. It is that second step that causes severe pathology and death, and once it is underway in earnest a patient's amyloid-β burden is of little relevance. This the explanation given for the lack of patient benefits resulting from the successful clearance of amyloid-β using forms of immunotherapy. The industry has now shifted to testing these treatments in patients at an earlier stage of Alzheimer's disease, and there are preliminary signs that this might be producing results. Even so, it may still be the case that amyloid-β is only a sidebar to other, more important disease mechanisms. Some researchers argue for chronic inflammation, driven by factors such as persistent viral infection, to be the true cause, for example.

Some researchers have long argued for starting amyloid immunotherapy early, before neurofibrillary tangles spread and neurons die all over the brain. They have recently added flesh to the bone of this idea. Despite coming from different anti-amyloid antibody therapies - donanemab, lecanemab, gantenerumab - the findings paint a convergent picture. In short, participants at the earliest stages of the respective cohorts enrolled in each trial gained the most cognitively from treatment. The findings are preliminary, often involving post hoc analyses of small numbers of participants remaining from large trials.

In one striking tease, about two-thirds of participants with very early Alzheimer's disease who took lecanemab actually improved on the Clinical Dementia Rating Scale Sum of Boxes Scores (CDR-SB) over 18 months, compared with about one-third of a matched placebo group. Other findings offered the first concrete indication that amyloid immunotherapy may be able to prevent Alzheimer's disease. In the Dominantly Inherited Alzheimer Network secondary prevention trial, presymptomatic mutation carriers taking gantenerumab for eight years had half the odds of developing symptoms as did those on placebo.

Link: https://www.alzforum.org/news/conference-coverage/treat-av-bothers-tau-scientists-say-ctad

Many large epidemiological studies demonstrate a correlation between cardiovascular aging and the risk of suffering cognitive decline and dementia. The population size of such studies has increased in recent years with the advent of sizable national databases, such as the UK Biobank. Today's open access paper focuses on one specific aspect of cardiovascular aging, the onset of atrial fibrillation, irregular heartbeats that can be accompanied by palpitations and other worrying sensations. Atrial fibrillation can arise in combination with many of the features of cardiovascular aging, and one might argue that data on time of diagnosis is interesting because the physical sensation of atrial fibrillation might more readily drive people to see a physician (and thus become a row in a database) than is the case for other early manifestations of declining heart function.

Regardless of that speculation, the researchers demonstrated that earlier diagnosis of atrial fibrillation, indicative in some fraction of cases that other cardiovascular issues are present, is associated with increased risk of suffering later dementia. The brain is an energy-hungry organ, and cardiovascular aging can imply reduced blood flow to the brain, a lower supply of nutrients that has consequences over the long term. That cardiovascular aging associated is typically also accompanied by a greater decline in quality of blood vessels and higher blood pressure, leading to damage and rupture of small vessels in the brain. There are numerous other mechanisms that likely contribute meaningfully to the link between heart, circulation, and brain, of course: nothing is ever simple in the biology of aging.

Age at Diagnosis of Atrial Fibrillation and Incident Dementia

To examine whether age at atrial fibrillation (AF) diagnosis is associated with risk of incident dementia and its subtypes, this prospective, population-based cohort study used data from UK Biobank, a public, open-access database in the UK with baseline information collected from 2006 to 2010. A total of 433,746 participants were included in the main analysis after excluding participants with a diagnosis of dementia or AF at baseline, missing data on covariates, or having dementia before AF onset during a median follow-up of 12.6 years. Data were analyzed from October to December 2022.

Our research showed that AF participants had an elevated risk of subsequent dementia compared with participants without AF. More importantly, multivariate Cox regression models indicated that an earlier diagnosis of AF was associated with greater risks of incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD). Additionally, the results remained robust after propensity score matching, reinforcing the fact that the probability of developing dementia increases with a younger onset age of AF.

Compared with individuals without AF, 30,601 individuals with AF had a higher risk of developing all-cause dementia (adjusted hazard ratio [HR], 1.42). Among participants with AF, younger age at AF onset was associated with higher risks of developing all-cause dementia (adjusted HR per 10-year decrease, 1.23), AD (adjusted HR per 10-year decrease, 1.27), and VD (adjusted HR per 10-year decrease, 1.35). After propensity score matching, individuals with AF diagnosed before age 65 years had the highest HR of developing all-cause dementia (adjusted HR, 1.82), followed by AF diagnosed at age 65 to 74 years (adjusted HR, 1.47) and diagnosed at age 75 years or older (adjusted HR, 1.11). Similar results can be seen in AD and VD.

To our knowledge, while current epidemiological studies still focus predominantly on the association between AF and subsequent cognitive decline or incident dementia, the present study is the largest study to explore the association between AF onset age and incident dementia. Based on accurate data on AF diagnoses and incident dementia, the most distinguished finding of our research was that an earlier diagnosis of AF was associated with an elevated risk of developing all-cause dementia, AD, and VD.

Glutathione is an interesting cellular antioxidant, as increased levels can improve health in humans and slow aging in animal models. You might recall recent small human trials of high dose supplementation of glutathione precursors in order to achieve upregulation of glutathione, and corresponding studies in mice. It is thought that glutathione upregulation may largely improve health via mitochondrial function, as mitochondria are a prominent source of oxidative stress in aging cells. Here, researchers find a mechanism that regulates the amount of glutathione that enters the mitochondria, and thus a possible target to increase this level without the need for global upregulation. Whether not it is capable of producing greater benefits remains to be seen.

Glutathione is an antioxidant produced throughout the body that plays many important roles, including neutralizing unstable oxygen molecules called free radicals, which cause damage to DNA and cells if left unchecked. It also helps repair cellular damage and regulates cell proliferation, and its loss is associated with aging, neurodegeneration, and cancer. As a result, glutathione supplements have become increasingly popular as an over-the-counter approach to wellness. The antioxidant is especially abundant in mitochondria, which cannot function without it. As the respiratory organelle, mitochondria produces energy, but mitochondria can also the source of a lot of oxidative stress, implicated in cancer, diabetes, metabolic disorders, and heart and lung diseases, among others. If glutathione levels aren't precisely maintained in mitochondria, all systems fail. None of us can survive without it.

How glutathione actually enters mitochondria was unknown until 2021, when researchers discovered that a transporter protein called SLC25A39 delivers the package. It also appeared to regulate the amount of glutathione. "When the antioxidants are low, the level of SLC25A39 increases, and when the antioxidant levels are high, the transport level goes down. Somehow a mitochondrion figures out how much antioxidant it has, and depending on that amount, it regulates the amount of antioxidant it lets inside."

To ferret out how mitochondria do it, researchers used a combination of biochemical studies, computational methods, and genetic screens to discover that SLC25A39 is both a sensor and a transporter at the same time. It has two completely independent domains. One domain senses the glutathione, and the other transports it. Now that the researchers know how SLC25A39's package delivery system operates, they can experiment with manipulating it. "This particular transporter protein is upregulated in a group of cancers. People have tried to change overall glutathione levels, but now we have a way to change it in mitochondria without impacting other parts of the cell. This kind of targeted therapy could potentially lower the number of side effects that can come with altering glutathione levels across the whole body."

Link: https://www.rockefeller.edu/news/34956-how-the-antioxidant-glutathione-keeps-mitochondria-healthy/

Phenotypic age is one of the less complicated biological age measures developed in recent years. As for all of the others, it was developed by using machine learning on a large set of human data, in this case commonly assessed blood biomarkers and their values at different ages. Thus while we know exactly what is being measured, it is an open question as to how those measurements relate to the underlying processes of aging, or indeed whether they accurately reflect all of those processes. Once one starts down the path of using lifestyle interventions to slow aging or novel therapies to repair the cell and tissue damage that causes aging, will phenotypic age usefully report the outcomes? Maybe it will, maybe it won't, and the answer may be different for every different type of intervention. The only way to be certain is to calibrate the biological age measure against actual outcomes, and the study noted here is a step in that direction.

Having high cardiovascular health may slow the pace of biological aging, which may reduce the risk of developing cardiovascular and other age-related diseases while extending life. Researchers examined the association between heart and brain health, as measured by the American Heart Association's Life's Essential 8 checklist and the biological aging process, as measured by phenotypic age.

Instead of a calendar to assess chronological (actual) age, phenotypic age is a robust measure of biological (physiological) age calculated based on your chronological age plus the results of nine blood markers (routinely captured during clinical visits) for metabolism, inflammation, and organ function (including glucose, C-reactive protein, and creatinine). Phenotypic age acceleration is the difference between one's phenotypic age and actual age. A higher phenotypic age acceleration value indicates faster biological aging.

After calculating phenotypic age and phenotypic age acceleration for more than 6,500 adults who participated in the 2015-2018 National Health and Nutrition Examination Survey (NHANES), the analysis found that participants with high cardiovascular health had a negative phenotypic age acceleration - meaning that they were younger than expected physiologically. In contrast, those with low cardiovascular health had a positive phenotypic age acceleration - meaning that they were older than expected physiologically. For example, the average actual age of those with high cardiovascular health was 41, yet their average biological age was 36; and the average actual age of those who had low cardiovascular health was 53, though their average biological age was 57.

After accounting for social, economic and demographic factors, having the highest Life's Essential 8 score (high cardiovascular health) was associated with having a biological age that is on average six years younger than the individual's actual age when compared to having the lowest score (low cardiovascular health).

Link: https://newsroom.heart.org/news/following-lifes-essential-8-checklist-may-slow-biological-aging-by-6-years

A small number of low-cost and generic drugs have extensive human use and safety data, but also a sizable, compelling body of animal study evidence to either (a) suggest a likely modest slowing of aging, e.g. rapamycin, or (b) demonstrate the ability to target a mechanism of aging to reverse age-related disease, e.g. the dasatinib and quercetin combination, shown to selectively destroy senescent cells. In the US any drug approved for a given use can also be used off-label to treat other conditions. In principle the drug can be prescribed by any physician in this way. This is legal, though tends to require a slow bootstrapping process of education, physician acceptance, gradual gathering of more data for the intended off-label use, and eventual grandstanding and interference by regulators.

It is an important process, though. Not just because it is a path to what are likely significant gains to health for the older end of the population, and not just because it is the only viable way to produce clinical data for generic drugs, as there is no financial incentive for industry to fund clinical trials of these treatments, but also because adoption drives public support for greater funding of research into treating aging as a medical condition, and greater investment in the longevity industry. At present, funding for aging research is a tiny anemic fraction of expenditure on medicine, and the longevity industry is minuscule compared to the broader biotech and medical industry. This is a ridiculous state of affairs given the staggering human and economic costs of aging, the vast and ongoing death toll, the hundreds of millions crippled by degenerative disease.

Philanthropists can play a role in speeding up the evaluation and adoption of low cost treatments like rapamycin and dasatinib and quercetin. Rather than leaving the present slow bootstrapping to run its course, a process that could easily consume another decade or two, matters can be accelerated by organizing informal but well-run trials in a few hundred individuals. The cost of this can be $500,000 to $1,000,000 or so per trial, we within the reach of many longevity-interested philanthropists. As a model, look at the PEARL trial crowdfunded by Lifespan.io, an example of how to do something meaningful in this space at a comparatively small expense. Such trials can be followed up with outreach to physician networks and patient advocacy groups, increasing the number of physicians willing to prescribe these treatments off-label. This would be a worthy exercise.

Is the Secret to a Longer Life Already Available at Your Local Pharmacy?

Depending on who you ask, we may be on the cusp of a great leap forward in longevity medicine. "In probably the next three to four years, you will have this pill basket" of anti-aging drugs. Based on the patient's health profile, a clinician could tap into the basket's selections and prescribe something to improve health during their final decades: "Let us see whether we can add 10 more years of a healthy life to you." You'd have to be remarkably bullish to believe those drugs will prove to greatly boost the quality and length of late life in the imminent future. There are doubts that the potential of these therapies will be fully understood - and thus implemented most effectively - any time soon. After all, proper testing would take decades. Yet some experts in the burgeoning field of geroscience are increasingly confident that a batch of different molecules undergoing analysis for anti-aging properties contains game-changers. Among the potential prize ponies are prescription drugs like rapamycin, metformin, and senolytics, alongside supplements like alpha-ketoglutarate and taurine. The aim is to perfect an array of molecules that not only extend the life expectancy of users, but also boost overall health during their final years.

But despite the potentially transformative nature of these molecules, some spectators have found progress to be needlessly slow. "The way our regulatory system is structured, there's just no incentive to do those trials." Because many of the promising candidates are already generic drugs, the rate of research has been gradual. Without serious money to make, even the prospect of a non-metaphorical Holy Grail can't motivate the pharmaceutical industry. The structure of FDA trials are also an awkward fit with geroscience. When testing the efficacy of an anti-aging therapy, what do you measure? There's not a catch-all biomarker. "If we go to the FDA with a blood pressure medication, we measure blood pressure to know if the drug is working or not. With aging, it's really hard to go with what marker you're going to use."

Nonetheless, progress has continued. Closely watching the advance are so-called biohacker communities, online groups that digest any new data to guide their own regimens of potential longevity drugs-typically therapies for other illnesses taken off-label - hoping for a headstart on treatments whose effectiveness will later be fully proven. The search for life-lengtheners has long attracted bunk science and charlatans, and the addition of outsider research - legitimate or not - could give medical experts pause. "That's something that the aging community is really wrestling with right now. Aging has really been pushed to the forefront, which is a good thing. But we're trying to get past the pseudoscience of the Fountain of Youth and that kind of thing."

But even as that tension persists, amateur discourse around these drugs may have the effect of drawing the attention of physicians. A primary feature of digital communities devoted to gerontology is to share where certain therapies may be procured. It provides not just an access point for future users, but it could also serve to reassure prospective prescribers. "There's a small group of them at first. But once they see some of their colleagues doing this - and maybe their colleagues have 100 or 500 patients on rapamycin - then they start to feel comfortable." Thus, as the online community of people allegedly taking these drugs grows, its relationship with the medical community becomes more reciprocal, and a given drug's credibility "percolates through the medical community that way."

There are now many ways to determine biological age, the most prevalent of which are epigenetic clocks and combinations of normal blood biomarkers such as the phenotypic age clock. In all cases, the idea is to identify specific measurable changes that correlate with age, and then develop an algorithm that combines the measures to produce an age as the output. Whether a given clock actually reflects all of the processes of aging, and what exactly is being measured under the hood, are questions that have yet to be satisfactorily answered. It has been noted that in all of the established biological age measures, people with a higher biological age than chronological age also exhibit a higher risk of age-related disease. This is the case here, for another novel measure of biological age that is derived from a combination of simple biomarkers.

In order to measure biological age and the link to disease, the researchers used data from the UK Biobank. They studied a cohort of 325,000 people who were all between 40 and 70 years old at the time of the first measurement. Biological age was calculated using 18 biomarkers, including blood lipids, blood sugar, blood pressure, lung function, and BMI. The researchers then investigated the relationship between these biomarkers and the risk of developing neurodegenerative diseases such as dementia, stroke, ALS, and Parkinson's disease within a nine-year period.

When compared to actual, chronological age, high biological age was linked to a significantly increased risk of dementia, especially vascular dementia, and ischemic stroke, (i.e. blood clot in the brain). "If a person's biological age is five years higher than their actual age, the person has a 40 per cent higher risk of developing vascular dementia or suffering a stroke." The results are particularly interesting because the study included such a large group of people. This makes it possible to break down the material into smaller pieces and capture less common diagnoses such as ALS. The risk of developing ALS also increases with higher biological age. However, no such risk increase was seen for Parkinson's disease.

Link: https://news.ki.se/high-biological-age-may-increase-the-risk-of-dementia-and-stroke

The Hallmarks of Aging were first published some years ago now, long enough to be expanded upon and much debated. The hallmarks are a list of characteristic changes in cell and tissue biochemistry noted to take place with advancing age, some of which are likely causes of age-related degeneration, some of which are likely downstream consequences, and all of which interact with one another. As often happens in such matters, the original hallmarks of aging drew from, and then eclipsed in terms of attention, the much earlier Strategies for Engineered Negligible Senescence (SENS) list of forms of cell and tissue damage that are causative of aging. In this review paper, researchers provide an overview of the subset of the hallmarks of aging that are not directly connected to the genome.

Aging is defined as a process in which there is a gradual loss of organ function and a reduction in the ability to regenerate. This is due to the multiple changes that occur at the molecular and cellular levels. Various theories have been formulated to explain the cause of aging, e.g., oxidative damage or programmed theory. These theories cover only a certain aspect of the aging process and do not consider its full complexity. The theory that connects all causes of aging is based on the hallmarks of aging, molecular processes that accumulate damage during aging that exceed the cell's ability to repair it.

The most significant changes at the genomic level (DNA damage, telomere shortening, epigenetic changes) and non-genomic changes are referred to as hallmarks of aging. The hallmarks of aging and cancer are intertwined. Many studies have focused on genomic hallmarks, but non-genomic hallmarks are also important and may additionally cause genomic damage and increase the expression of genomic hallmarks. Understanding the non-genomic hallmarks of aging and cancer, and how they are intertwined, may lead to the development of approaches that could influence these hallmarks and thus function not only to slow aging but also to prevent cancer. In this review, we focus on non-genomic changes. We discuss cell senescence, disruption of proteostasis, deregualation of nutrient sensing, dysregulation of immune system function, intercellular communication, mitochondrial dysfunction, stem cell exhaustion, and dysbiosis.

Link: https://doi.org/10.3390/ijms242015468

In recent years, a number of epidemiological studies have demonstrated that people with healthier lifestyles tend to live longer, at least within the bounds of later life from 60 to 100. That in turn is reflected by a lesser burden of various forms of cell and tissue damage, such as the accumulation of senescent cells. This isn't a controversial statement, though there is room enough to argue for an eternity over just how large the effect of any specific choice might be, how that effect size varies between populations, how different choices combine, and so forth. Then on top of all of this, the question of what happens and why in extreme old age past 100 exists in its own realm of comparatively little data because of the low survival to such advanced ages.

Arguably we shouldn't much care about centenarians and the fine details of the various lifestyle and biological contributions to their survival odds, as it is much akin to asking why some people managed to die more slowly when infected with tuberculosis prior to the development of effective antibiotics. That question isn't the right focus for the problem. The right focus for aging is on the common root cause mechanisms that conspire to kill everyone, and on reversing those mechanisms such that no-one is killed by them. Understanding how some people manage to resist the cell and tissue damage of aging for a longer rather than a shorter span of years is irrelevant in comparison to understanding how to repair that damage.

The first rejuvenation therapies, in the form of first generation senolytics such as the dasatinib and quercetin combination, exist, are available to the adventurous, and are taking a surprisingly long time to emerge into a wider appreciation of their potential. The rest of the package of biotechnologies needed for human rejuvenation are going to take an appreciable amount of time to arrive in the clinic, perhaps several decades at this point, barring a major shift in the way in which medical regulation works. So if one can add a few years by making smarter lifestyle choices, then why not? It isn't any big secret as to what those choices are: regular exercise, strength training, calorie restriction of some form, and avoiding the many forms of readily available self-sabotage such as smoking.

Lifestyle interventions to delay senescence

Senescence is a condition of cell cycle arrest that increases inflammation and contributes to the development of chronic diseases in the aging human body. The beneficial role of senescent cells early in life can become detrimental in later years. The accumulation of senescent cells with time reduces the capacity of the body to regenerate and induces chronic inflammation via the senescence-associated secretory phenotype (SASP), which contributes to the condition of inflammaging during the aging process and especially in older adults. While senotherapies capable of clearing senescent cells have emerged as potential treatments for chronic diseases, less attention has been devoted to the effects of lifestyle interventions that are widely available, easy to implement, and safe when used as recommended.

Exercise is widely recognized to produce beneficial effects on health of animals and humans. Several preclinical studies indicate that exercise can reduce the number of senescent cells in various organs including the heart, liver, muscles, kidneys, and adipose tissues. For instance, wheel running for three weeks reduced the senescence marker p16 in the heart of mice. Aerobic treadmill exercise for 15-60 minutes daily, five times per week for six weeks reduced levels of senescence-associated beta-galactosidase in the kidneys of aged mice. Similarly, a three-month swimming program reduced senescence markers and the pro-inflammatory cytokine interleukin-6 (IL-6) in the liver of rodents treated with d-galactose to induce aging. However, the high heterogeneity of exercise regimens used in these animal models and the sole reliance on senescence markers limit our understanding of the mechanisms underlying the effects of exercise on senescence.

In humans, regular physical activity for at least 4 hours per month is associated with reduced levels of p16INK4 in T lymphocytes. A five-month training program reduced the number of p16INK4-positive senescent cells in thigh adipose tissues of older overweight women. Expression of p16 and IL-6 was elevated in the colonic mucosa of middle-aged and older overweight men compared to young sedentary men, whereas this elevation was blunted in age-matched endurance runners with several years of experience. Similarly, the increase of senescent endothelial cells and impaired vascular endothelial function observed in brachial arteries of older sedentary individuals was absent in older exercising subjects.

Different lifestyle interventions including exercise, nutrition, intermittent fasting, and consumption of phytochemicals, prebiotics and probiotics, and adequate sleep can produce anti-senescence effects in model organisms and humans. Given the widespread beneficial effects of these lifestyle interventions, the findings described here are perhaps not surprising - except that the reduction of senescent cells represents a new mechanism of action to explain the effects of these interventions. The effects of lifestyle factors on senescence are quite complex and can easily be neutralized or become detrimental depending on their intensity and frequency. Moreover, an unhealthy lifestyle involving sedentarity, consumption of excess alcohol, smoking, lack of sleep and sunlight exposure and chronic stress may offset some of the beneficial effects of other interventions on senescence. More attention should therefore be given to the modalities that produce beneficial effects and their interactions with anti-senescence compounds and other lifestyle habits.

TREM2 is most studied in the context of Alzheimer's disease and related forms of neurodegeneration, where it seems to affect inflammation driven by microglia and loss of the ability of microglia to clear amyloid-β from the aging brain. Microglia are, more or less, the central nervous system version of the innate immune cells called macrophages that are found throughout the rest of the body. Atherosclerosis is the largest cause of human mortality, and is driven by macrophage dysfunction. Macrophages are responsible for clearing excess lipids from blood vessel walls, but when these cells become overwhelmed by local excesses of lipids they become inflammatory, contributing to the growth of atherosclerotic plaques rather than helping the situation. As noted here, it appears that TREM2 is involved in this process, affecting the capacity of macrophages to resist the plaque environment.

Atherosclerosis is driven by the expansion of cholesterol-loaded 'foamy' macrophages in the arterial intima. Factors regulating foamy macrophage differentiation and survival in plaque remain poorly understood. Here we show, using trajectory analysis of integrated single-cell RNA sequencing data and a genome-wide CRISPR screen, that triggering receptor expressed on myeloid cells 2 (Trem2) is associated with foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up oxidized low-density lipoprotein (oxLDL). Myeloid-specific deletion of Trem2 showed an attenuation of plaque progression, even when targeted in established atherosclerotic lesions, and was independent of changes in circulating cytokines, monocyte recruitment, or cholesterol levels.

Mechanistically, we link Trem2-deficient macrophages with a failure to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival. Overall, we identify Trem2 as a regulator of foamy macrophage differentiation and atherosclerotic plaque growth and as a putative therapeutic target for atherosclerosis.

Link: https://doi.org/10.1038/s44161-023-00354-3

A white matter hyperintensity is a small areas of tissue damage in the brain, such as results from rupture of a small blood vessel and consequent bleeding. These areas of damage are readily visible in MRI scans, and their prevalence is known to correlate with loss of cognitive function and rising dementia risk. Here, researchers provide evidence to suggest that this process is primarily the result of amyloid-β aggregation in the brain rather than vascular aging processes.

Bright spots called white-matter hyperintensities (WMHs) often appear on MRI scans of people with familial or sporadic Alzheimer's disease (AD), and they tend to intensify as the disease progresses. Some scientists think they reflect cerebrovascular disease. However, researchers now offer a different explanation. They reported that WMHs worsened most in people with extensive neurodegeneration, amyloid plaques, or cerebral microbleeds, a sign of cerebral amyloid angiopathy (CAA), while WMH severity did not correlate with vascular risk. They concluded that WMHs are driven by AD pathology.

Researchers compared the total volume of WMHs to cardiovascular risk, as measured by the Framingham Heart Study cardiovascular disease risk score, and to the amount of amyloid, be it plaques or CAA. Researchers drew data from clinical records and almost 4,000 brain scans of 1,141 people from three longitudinal cohorts: the Harvard Aging Brain Study, the Alzheimer's Disease Neuroimaging Initiative, and the Dominantly Inherited Alzheimer Network. At baseline, WMH volume was greatest among those who were oldest, had the least gray matter, the highest amyloid burden, or who had two or more cerebral microbleeds, a commonly used indicator of CAA that can only be diagnosed at autopsy. Over time, WMHs worsened more among these people than among their respective controls.

This fits with the idea that amyloid constricts blood vessels. Researchers have found that soluble amyloid-β slowed cerebral blood flow in wild-type and amyloidosis mice and that vascular injury can be prevented if reactive oxygen species (ROS) scavengers are administered before the peptide settles into vessels as CAA. ROS are a major cause of vessel damage by amyloid-β. Did vascular health factor into WMH severity? Surprisingly, the amount of WMHs had no correlation with cardiovascular risk score after accounting for age, gray-matter volume, amyloid burden, and cerebral microbleeds. The authors concluded that amyloid and gray-matter atrophy, i.e., neurodegeneration, drives the brain lesions rather than small-vessel disease.

Link: https://www.alzforum.org/news/research-news/amyloid-not-vascular-disease-may-drive-white-matter-hyperintensities

It is uncontroversial to point out that exercise is good for long-term health. It slows aging, reduces risk of age-related disease, reduces mortality. A mountain of evidence supports these assertions, both animal studies demonstrating causation, and any number of large human studies showing correlation. Exercise, like the practice of calorie restriction, produces sweeping changes in the operation of metabolism. Near everything is different, both in the short term following exercise, and over the long term when looking at differences between the biochemistry of a fit individual versus that a sedentary individual. This can make it hard to determine which of the countless specific changes are important, or where they sit in the network of cause and effect.

Cellular biochemistry remains incompletely understood and explored. There is plenty of room to take even a very well studied subject, such as the beneficial effects of exercise, and find something novel to say about it. In today's research materials, scientists discuss a recent discovery related to the role of the immune system in mediating some of the benefits to health that result from exercise, such as reductions in inflammatory signaling. Given the age-related decline of the immune system, and the chronic inflammation of aging, it is interesting to consider how this part of the response to exercise likely breaks down with age.

Some benefits of exercise stem from the immune system

Most previous research on exercise physiology has focused on the role of various hormones released during exercise and their effects on different organs such as the heart and the lungs. A new study unravels the immunological cascade that unfolds inside the actual site of exertion - the muscle. Exercise is known to cause temporary damage to the muscles, unleashing a cascade of inflammatory responses. It boosts the expression of genes that regulate muscle structure, metabolism, and the activity of mitochondria, the tiny powerhouses that fuel cell function. Mitochondria play a key role in exercise adaptation by helping cells meet the greater energy demand of exercise. In the new study, the team analyzed what happens in cells taken from the hind-leg muscles of mice that ran on a treadmill once and animals that ran regularly. Then, the researchers compared them with muscle cells obtained from sedentary mice.

The muscle cells of the mice that ran on treadmills, whether once or regularly, showed classic signs of inflammation - greater activity in genes that regulate various metabolic processes and higher levels of chemicals that promote inflammation, including interferon. Both groups had elevated levels of regulatory T cells (Treg cells) in their muscles. Further analyses showed that in both groups, Tregs lowered exercise-induced inflammation. None of those changes were seen in the muscle cells of sedentary mice. However, the metabolic and performance benefits of exercise were apparent only in the regular exercisers - the mice that had repeated bouts of running. In that group, Tregs not only subdued exertion-induced inflammation and muscle damage, but also altered muscle metabolism and muscle performance, the experiments showed. This finding aligns with well-established observations in humans that a single bout of exercise does not lead to significant improvements in performance and that regular activity over time is needed to yield benefits.

Further analyses confirmed that Tregs were, indeed, responsible for the broader benefits seen in regular exercisers. Animals that lacked Tregs had unrestrained muscle inflammation, marked by the rapid accumulation of inflammation-promoting cells in their hindleg muscles. Their muscle cells also had strikingly swollen mitochondria, a sign of metabolic abnormality. More importantly, animals lacking Tregs did not adapt to increasing demands of exercise over time the way mice with intact Tregs did. They did not derive the same whole-body benefits from exercise and had diminished aerobic fitness. These animals' muscles also had excessive amounts of interferon, a known driver of inflammation. Further analyses revealed that interferon acts directly on muscle fibers to alter mitochondrial function and limit energy production. Blocking interferon prevented metabolic abnormalities and improved aerobic fitness in mice lacking Tregs. "The villain here is interferon. In the absence of guardian Tregs to counter it, interferon went on to cause uncontrolled damage. We've only looked in the muscle, but it's possible that exercise is boosting Treg activity elsewhere in the body as well."

Regulatory T cells shield muscle mitochondria from interferon-γ-mediated damage to promote the beneficial effects of exercise

Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. Although some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure. Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models in mice. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against overexuberant production of interferon-γ and consequent metabolic disruptions, particularly mitochondrial aberrancies. The performance-enhancing effects of exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.

Circulating oxytocin levels decline with age, and a number of research groups have demonstrated that oxytocin upregulation produces benefits in animal studies. Here, researchers provide evidence for a species of bacteria resident in the intestine to contribute to changes in oxytocin expression and secretion. As the balance of different microbial populations of the gut change with age, this might lead to ways to restore more youthful levels of oxytocin in the body via manipulation of the gut microbiome.

The gut microbiome, a community of trillions of microbes living in the human intestines, has an increasing reputation for affecting not only gut health but also the health of organs distant from the gut. For most microbes in the intestine, the details of how they can affect other organs remain unclear, but for gut resident bacteria L. reuteri the pieces of the puzzle are beginning to fall into place. Researchers have found that these bacteria reduce gut inflammation in adult humans and rodent models, suppress bone loss in animal models of osteoporosis and in a human clinical trial, promote skin wound healing in mice and humans and improve social behavior in six mouse models of autism spectrum disorder.

Of those effects of L. reuteri, the abilities to promote social behavior and wound healing have been shown to require signaling by the hormone oxytocin, but little was known about how this occurs. "Oxytocin is mostly produced in the hypothalamus, a brain region involved in regulating feeding and social behavior, as well as in other organs. Given that other brain-produced hormones also are made in the gut, we tested the novel idea that oxytocin itself was also produced in the intestinal epithelium where L. reuteri typically resides."

The researchers built up their case step by step. First, they reviewed single-cell RNA-Seq datasets of the intestinal epithelium, which show which genes are expressed in that tissue. They found that oxytocin genes are expressed in the epithelium of various species, including mice, macaques, and humans. Then, using fluorescence microscopy, the team revealed the presence of oxytocin directly on human intestinal organoids, also called mini guts, which are laboratory models of intestinal tissue that recapitulate many of its functions and structure. "We also determined a mechanism by which L. reuteri mediates oxytocin secretion from human intestinal tissue and human intestinal organoids. L. reuteri stimulates enteroendocrine cells in the intestine to release the gut hormone secretin, which in turn stimulates another intestinal cell type, the enterocyte, to release oxytocin."

Link: https://blogs.bcm.edu/2023/11/02/from-the-labs-research-connecting-gut-bacteria-and-oxytocin-provides-a-new-mechanism-for-microbiome-promoted-health-benefits/

Both epigenetic clocks to measure biological age and the impact of the gut microbiome on long-term health and aging are areas of active and ongoing research. So naturally there will be studies linking the two, attempting to show correlations between specific age-related changes in the microbial populations of the gut and measures of biological age such as epigenetic clocks based on DNA methylation. At some point this will lead to, most likely, some form of aggressive, high-dose, complicated probiotic therapy consisting of many different microbial species that will result in an optimal gut microbiome, reducing inflammation and the production of harmful metabolites in older individuals. Before that emerges, however, the fecal microbiota transplant of a healthy young microbiome into an older individual appears workable, readily available, and beneficial, given the evidence to date.

The causal relationship between gut microbiota and DNA methylation phenotypic age acceleration remains unclear. This study aims to examine the causal effect of gut microbiota on the acceleration of DNA methylation phenotypic age using Mendelian randomization. A total of 212 gut microbiota were included in this study, and their 16S rRNA sequencing data were obtained from the Genome-wide Association Study (GWAS) database. The GWAS data corresponding to DNA methylation phenotypic age acceleration were selected as the outcome variable. Two-sample Mendelian randomization (TSMR) was conducted.

The results from inverse-variance weighting (IVW) analysis revealed significant associations between single nucleotide polymorphisms (SNPs) corresponding to 16 gut microbiota species and DNA methylation phenotypic age acceleration. Out of the total, 12 gut microbiota species exhibited consistent and robust causal effects. Among them, 7 displayed a significant positive correlation with the outcome while 5 species showed a significant negative correlation with the outcome. This study utilized Mendelian randomization to unravel the intricate causal effects of various gut microbiota species on DNA methylation phenotypic age acceleration.

Link: https://doi.org/10.1038/s41598-023-46308-4

T cell exhaustion occurs in aging, but also in circumstances in which the adaptive immune system is constantly stimulated over time, such as in cases of persistent HIV infection, or the presence of solid tumors. An exhausted T cell has adopted a state in which it is functionally incapable, no longer responsive to antigens. Ways to reverse T cell exhaustion would be very beneficial, and so the research community has made some inroads in understanding the mechanisms of exhaustion, enough to produce proof of concept approaches, such as those involving epigenetic reprogramming, BAFT upregulation, TIGIT knockdown, and various small molecules identified in screening programs.

In today's research materials, scientists provide evidence for T cell exhaustion to be caused by mitochondrial dysfunction. Thus ways to maintain or restore mitochondrial function will allow cells to resist the exhausted state. This may explain the success that researchers have had with epigenetic reprogramming in the context of T cell exhaustion, as this intervention is well known to restore mitochondrial function. Overall, this finding is quite interesting in the context of age-related T cell exhaustion, given the mitochondrial dysfunction that occurs with advancing age. It suggests that all strategies that can improve mitochondrial function may produce corresponding gains in immune function.

Preventing the Exhaustion of T Cells

When mitochondrial respiration fails, a cascade of reactions is triggered, culminating in the genetic and metabolic reprogramming of T cells - a process that drives their functional exhaustion. But this "burnout" of the T cells can be counteracted: pharmacological or genetic optimization of cellular metabolism increases the longevity and functionality of T cells. This can be achieved, for example, by overexpressing a mitochondrial phosphate transporter that drives the production of the energy-providing molecule adenosine-triphosphate.

"It was commonly assumed that the observed alterations in the mitochondrial metabolism were a consequence of T-cell exhaustion." To demonstrate that mitochondrial dysfunction is the actual cause of T cell exhaustion, researcher developed a new genetic model. It switches off the mitochondrial phosphate transporter (SLC25A3) and paralyses mitochondrial respiration in T cells. As a result, the T cells are forced to switch to alternative metabolic pathways, mainly aerobic glycolysis, to meet their bioenergetic demand in the form of adenosine triphosphate. However, this metabolic adaptation causes an increased production of reactive oxygen species in the T cells.

Elevated levels of oxygen radicals prevent the degradation of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1-alpha). The accumulation of HIF-1-alpha protein causes a genetic and metabolic reprogramming of the T cells, accelerating their exhaustion. "This HIF-1-alpha-dependent control of T-cell exhaustion was previously unknown. It represents a critical regulatory circuit between mitochondrial respiration and T cell function, serving as a 'metabolic checkpoint' in the process of T-cell exhaustion."

Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells.

At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

Researchers here find an approach to selective upregulation of CXCR4 that acts to suppress the development of atherosclerosis in a mouse model. It is a small molecule treatment, so may well make its way into further development. Like all such treatments, however, it will likely prove to have little effect on established atherosclerotic plaques. It remains to be seen as to whether the research and development community can bring effective means of reversal of atherosclerosis to the clinic in the years ahead. Efforts to produce therapies capable of reversal have to date near all focused on enhancing reverse cholesterol transport, and subsequently failed in clinical trials. Meanwhile most new drug development in the cardiovascular field remains fixated on lowering LDL cholesterol in the bloodstream, an approach that cannot reverse existing plaque. New ways forward are much needed.

Researchers have in the past demonstrated that the transmembrane protein CXCR4 plays a significant role in the development of atherosclerosis. The protein transmits signals to the cell interior. If CXCR4 is specifically silenced in arterial endothelial cells or in smooth muscle cells, it results in more severe atherosclerotic lesions. At the same time, there is increased leukocyte ingress into the cell, which leads to inflammatory processes. With regard to leukocytes, however, the presence of CXCR4 can also promote the development of inflammatory processes.

The researchers therefore searched specifically for microRNA molecules that are limited to vascular cells and are involved in the regulation of CXCR4. And indeed, they managed to identify a good therapeutic starting point for the treatment of atherosclerosis in the form of miR-206, a candidate which occurs only in endothelial cells and in vascular smooth muscle cells. In those sites, it downregulates the expression of CXCR4 by binding to the transcripts of the CXCR4 gene and preventing their conversion into the protein.

For therapeutic application, the effect of miR-206 needs to be suppressed. To this end, the researchers developed a so-called target-site blocker: a molecule that specifically interrupts interactions between miR-206 and the CXCR4 transcripts and thus only boosts its expression in the respective cells. The researchers were able to demonstrate the effectiveness of this approach in a mouse model and in human cells in the culture. Most notably, the blocker they developed was able to prevent atherosclerosis in the mouse model.

Link: https://www.lmu.de/en/newsroom/news-overview/news/atherosclerosis-rna-fragment-creates-prospect-for-new-therapies.html

Evidence suggests that enhanced DNA repair may act to slow the progression of aging. Researchers here note that increased levels of the metabolite guanosine triphosphate (GTP), a building block and energy source used in a variety of ways in the cell, can improve the pace of DNA repair. There are numerous ways by which GTP levels might be upregulated over the long term, but as researchers here note, the opposite is desirable in the case of cancer, in order to impair DNA repair and make cancerous cells more vulnerable to genotoxic therapies.

Researchers have long known that levels of nucleotides like GTP control how fast DNA damage is repaired, which in turn controls sensitivity to therapies. Researchers previously thought that this only happened because nucleotides are the building blocks that form DNA. But these findings uncover an entirely new way that nucleotides control DNA repair. "GTP impacts resistance or sensitivity to treatment not just because it's a building block of DNA, as we previously thought. Instead of only affecting the physical structure of the DNA, it also acts as a signaler. The levels of GTP turn on a signaling pathway and give cells instructions to repair damaged DNA."

"In the future, we'd like to develop therapeutics that leverage the relationship between GTP and DNA damage response, both to make cancer cells more sensitive to chemotherapy and radiation and also to boost GTP levels to protect normal tissue from damage. We knew that depleting GTP might make brain cancers respond better to chemotherapy and radiotherapy. Now these findings show why that's happening." The discovery that GTP acts as a signaler helps explain the biological underpinnings of why focusing on GTP is a worthwhile pursuit and could help researchers figure out which patients will derive the most benefit from GTP modulators in the clinical trial.

Link: https://www.michiganmedicine.org/health-lab/metabolite-tells-cells-whether-repair-dna

Compelling evidence obtained from many studies in mice show that the accumulation of senescent cells with age is a major contributing factor in all of the common, inflammatory age-related conditions: cardiovascular disease, dementia, degeneration of bone tissue, and so forth. Senescent cells are created throughout life, mostly as somatic cells reach the Hayflick limit on replication, but accumulate in later life in large part because the immune system falters in its clearance of senescent cells. It still performs this function, but less efficiently, and the balance between creation and destruction of senescent cells tips to allow growing numbers of senescent cells to accumulate in tissues throughout the body. Senescent cells energetically secrete pro-inflammatory signals, and this signaling maintained over the long term is highly disruptive to tissue structure and function. It is a contributing cause of aging.

The animal data for the use of senolytic therapies to clear senescent cells is very compelling. Researchers have demonstrated rapid reversal of many aspects of aging and age-related conditions in mice. The results are impressive, larger, and more easily replicated than those produced by any other strategy to date, through epigenetic reprogramming may catch up as it becomes more widely assessed in the research community. There is a strong argument for greater investment in clinical trials for the proven first generation senolytic therapies, low-cost existing drugs and supplements such as the dasatinib and quercetin combination, that offer the near future possibility of additional years of healthy life for the entire elderly population. While many companies are working towards second generation senolytic therapies, it will be a long time yet before these treatments are in the clinic, or, once in the clinic, actually available at low cost for large numbers of people.

Cellular senescence in skeletal disease: mechanisms and treatment

Age-related musculoskeletal diseases such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IDD) critically affect the motor functions and quality of life of elderly individuals. Unfortunately, although various drugs, (such as bisphosphonates, recombinant human parathyroid hormone, denosumab for OP, and paracetamol for OA), have been approved for use, their benefits are limited due to side effects or the poor overall health of elderly individuals. Aging involves complex mechanisms, including genetic mutations, telomere shortening, epigenetic alterations, protein deformation, mitochondrial damage, and cellular senescence, which are responsible for the onset of age-related diseases. Thus, investigating and manipulating the mechanisms underlying aging are important future research goals. Among the fundamental mechanisms mentioned above, cellular senescence has received considerable attention in recent years.

Cellular senescence refers to the stable condition of cell cycle arrest, first described in the early 1960s. Senescent cells (SnCs) are produced in the early stages of embryonic development and accumulate with age. However, SnCs exert deleterious effects on tissues by secreting a plethora of inflammatory cytokines, chemokines, oxidative stress-related proteins, growth factors, and proteases, which is termed the senescence-associated secretory phenotype (SASP). Accumulated SnCs are a hallmark of aging and contribute to age-related diseases, including OP, diabetes, and Alzheimer's disease. Interestingly, SnCs have dual effects on tumour development, which may depend on the immune microenvironment or cell cycle stage, as cell cycle arrest is helpful for tumour suppression.

The skeletal system consists of bones, joints, cartilage tissues, and ligaments that work together to maintain homeostasis of the motor system and the internal environment. Bone remodeling occurs throughout life. Bone tissue comprises four types of cells: osteoblasts, osteoclasts, osteocytes, and osteoprogenitors. They undergo fundamental changes during the aging process. Senescent mesenchymal stem cells (MSCs) exhibit decreased osteogenesis and increased adipogenesis, moreover, senescent osteocytes or osteoclasts produce SASP. However, the underlying mechanisms by which SnCs and SASP regulate bone remodelling and induce disease are still under investigation. In this review, we summarise the role of senescence in the skeletal system, discuss its underlying mechanisms, and propose new strategies for treating age-related diseases by targeting senescence.

When culturing any type of cell, the culture media contents come to reflect the secreted molecules and extracellular vesicles of that cell type - what is called "conditioned media". It is a snapshot of the communications produced by the cell type in its current state. First generation stem cell therapies, in which the transplanted cells die rather than integrate with tissues in any useful number, influence health via the effects of their secretions and vesicles on native cells. It is much easier to build therapies based on the contents of the media rather than it is to transplant the cells themselves, from the perspective of storage, readiness, consistency of production, and so forth, and so this is the direction that the clinical industry has been taking for some years. Of course, nothing involving cells is ever simple, as this review notes.

Recently published studies suggest that the paracrine substances released by mesenchymal stem cells (MSCs) are the primary motive behind the therapeutic action reported in these cells. Pre-clinical and clinical research on MSCs has produced promising outcomes. Furthermore, these cells are generally safe for therapeutic use and may be extracted from a variety of anatomical regions. Recent research has indicated, however, that transplanted cells do not live long and that the advantages of MSC treatment may be attributable to the large diversity of bioactive substances they create, which play a crucial role in the control of essential physiological processes.

Secretome derivatives, such as conditioned media or exosomes, may provide significant benefits over cells in terms of manufacture, preservation, handling, longevity of the product, and potential as a ready-to-use biologic product. Despite their immunophenotypic similarities, the secretome of MSCs appears to vary greatly depending on the host's age and the niches in which the cells live. The secretome's effect on multiple biological processes such as angiogenesis, neurogenesis, tissue repair, immunomodulation, wound healing, anti-fibrotic, and anti-tumor for tissue maintenance and regeneration has been discovered. Defining the secretome of cultured cultivated MSC populations by conditioned media analysis will allow us to assess its potential as a novel treatment approach.

This review will concentrate on accumulating data from pre-clinical and clinical trials pointing to the therapeutic value of the conditioned medium. At last, the necessity of characterizing the conditioned medium for determining its potential for cell-free treatment therapy will be emphasized in this study.

Link: https://doi.org/10.33549/physiolres.935186

The use of electromagnetic fields to manipulate cell activity is understudied in comparison to the use of small molecules, so it is always possible that meaningfully beneficial electromagnetic therapies might be awaiting discovery. The present lack of said therapies may be much more a matter of the lack of funding and experienced research groups needed for exploration and follow through rather than either an inherently greater difficulty in developing such therapies or an inherent lack of potential in this strategy. Here, researchers discuss whether one can use electromagnetism to manipulate the function and quality control mechanisms of mitochondria for therapeutic benefit, presenting a viewpoint that is sympathetic to the idea that research into electromagnetic therapies is inherently more challenging.

Mitohormesis is a process whereby mitochondrial stress responses, mediated by reactive oxygen species (ROS), act cumulatively to either instill survival adaptations (low ROS levels) or to produce cell damage (high ROS levels). The mitohormetic nature of extremely low-frequency electromagnetic field (ELF-EMF) exposure thus makes it susceptible to extraneous influences that also impinge on mitochondrial ROS production and contribute to the collective response. Consequently, magnetic stimulation paradigms are prone to experimental variability depending on diverse circumstances.

The failure, or inability, to control for these factors has contributed to the existing discrepancies between published reports and in the interpretations made from the results generated therein. Confounding environmental factors include ambient magnetic fields, temperature, the mechanical environment, and the conventional use of aminoglycoside antibiotics. Biological factors include cell type and seeding density as well as the developmental, inflammatory, or senescence statuses of cells that depend on the prior handling of the experimental sample. Technological aspects include magnetic field directionality, uniformity, amplitude, and duration of exposure. All these factors will exhibit manifestations at the level of ROS production that will culminate as a unified cellular response in conjunction with magnetic exposure. Fortunately, many of these factors are under the control of the experimenter.

This review will focus on delineating areas requiring technical and biological harmonization to assist in the designing of therapeutic strategies with more clearly defined and better predicted outcomes and to improve the mechanistic interpretation of the generated data, rather than on precise applications. This review will also explore the underlying mechanistic similarities between magnetic field exposure and other forms of biophysical stimuli, such as mechanical stimuli, that mutually induce elevations in intracellular calcium and ROS as a prerequisite for biological outcome. These forms of biophysical stimuli commonly invoke the activity of transient receptor potential cation channel classes, such as TRPC1.

Link: https://doi.org/10.3390/bioengineering10101176

The present consensus on the evolution of aging is that it is an inevitable side effect of natural selection - aging isn't selected for per se, it is a byproduct. Evolution favors reproduction earlier in life rather than later in life, particularly in environments with high mortality due to disease or predation, and thus there is little pressure to select for mutations that enhance long-term maintenance of the body and brain. Looking at the examples of biology around us, the outcome of this process is near always biological systems that fail over time, in which their structure is optimized for early life success at the cost of late life health. This state of affairs is called antagonistic pleiotropy, that many (even most) biological features are great for health when young, terrible for health when old.

This consensus is not without its heretics, those who argue that aging is under selection, that degeneration of the individual is in some way advantageous to fitness of the species. This is often called "programmed aging". It is argued to occur, for example, because aging species might better adapt to periodic sizable environment changes, or as a result of group selection effects such a continual reduction of the breeding population via aging minimizing the odds of a population explosion. Many of these arguments are presented in the form of a model, and that is the case in today's open access paper. Whether the argument is interesting or not tends to depend on the fine details of the assumptions baked into the model, and is rarely apparent at a summary level.

Directional selection coupled with kin selection favors the establishment of senescence

Conventional wisdom in evolutionary theory considers aging as a non-selected byproduct of natural selection. Based on this, conviction aging was regarded as an inevitable phenomenon. It was also thought that in the wild organisms tend to die from diseases, predation, and other accidents before they could reach the time when senescence takes its course. Evidence has accumulated, however, that aging is not inevitable and there are organisms that show negative aging even. Furthermore, old age does play a role in the deaths of many different organisms in the wild also. The hypothesis of programmed aging posits that a limited lifespan can evolve as an adaptation (i.e., positively selected for) in its own right, partly because it can enhance evolvability by eliminating "outdated" genotypes. A major shortcoming of this idea is that non-aging sexual individuals that fail to pay the demographic cost of aging would be able to steal good genes by recombination from aging ones.

Here, we show by a spatially explicit, individual-based simulation model that aging can positively be selected for if a sufficient degree of kin selection complements directional selection. Under such conditions, senescence enhances evolvability because the rate of aging and the rate of recombination play complementary roles. The selected aging rate is highest at zero recombination (clonal reproduction). In our model, increasing extrinsic mortality favors evolved aging by making up free space, thereby decreasing competition and increasing drift, even when selection is stabilizing and the level of aging is set by mutation-selection balance. Importantly, higher extrinsic mortality is not a substitute for evolved aging under directional selection either. Reduction of relatedness decreases the evolved level of aging; chance relatedness favors non-aging genotypes. The applicability of our results depends on empirical values of directional and kin selection in the wild.

We found that aging can positively be selected for in a spatially explicit population model when sufficiently strong directional and kin selection prevail, even if reproduction is sexual. The view that there is a conceptual link between giving up clonal reproduction and evolving an aging genotype is supported by computational results.

Chromatin is the bundled, packaged form of DNA found in the cell nucleus. The behavior of a cell depends on the precise details of the structure adopted by chromatin, because only exposed sequences of DNA can be used to produce proteins - the rest is hidden from the machinery of gene expression. The produced proteins can then lead to adjustments to chromatin structure, and thus a cell is in a constant state of change and feedback between chromatin structure, gene expression, protein activities, and the surrounding environment. Talking about chromatin structure in the context of aging is a very broad topic, much akin to talking about gene expression in the context of aging. Clearly there are changes, a lot of them. Clearly it is very complex. One can still find starting points for a discussion, however.

Chromatin provides an interface between genetic information and the environment, allowing an individual's experiences to shape the course of their life from within their cells. In order to store and protect genetic material, DNA is wrapped around histone proteins inside the nucleus, and this bundle of DNA and histones is termed chromatin. Histones do more than simply package DNA however, as the level of accessibility versus condensation of chromatin can impact the availability of DNA to binding by transcriptional machinery and therefore the expression of genes.

Aging affects nearly all aspects of our cells, from our DNA to our proteins to how our cells handle stress and communicate with each other. Age-related chromatin changes are of particular interest because chromatin can dynamically respond to the cellular and organismal environment, and many modifications at chromatin are reversible. Changes at chromatin occur during aging, and evidence from model organisms suggests that chromatin factors could play a role in modulating the aging process itself, as altering proteins that work at chromatin often affect the lifespan of yeast, worms, flies, and mice. The field of chromatin and aging is rapidly expanding, and high-resolution genomics tools make it possible to survey the chromatin environment or track chromatin factors implicated in longevity with precision that was not previously possible.

In this review, we discuss the state of chromatin and aging research. We include examples from yeast, Drosophila, mice, and humans, but we particularly focus on the commonly used aging model, the worm Caenorhabditis elegans, in which there are many examples of chromatin factors that modulate longevity. We include evidence of both age-related changes to chromatin and evidence of specific chromatin factors linked to longevity in core histones, nuclear architecture, chromatin remodeling, and histone modifications.

Link: https://doi.org/10.3389/fmolb.2023.1270285

Osteoarthritis is a degenerative joint disease characterized by loss of cartilage and associated bone tissue. It is a major, widespread issue in old age. A promising study in mice here suggests that osteoarthritis might be reversed via suitable manipulation of stem cell and progenitor cell populations capable of producing cartilage regrowth. In this model, the known contributing factors, such as chronic inflammation in and around joint tissues, are contributing factors because they suppress the activity of the small population of cells responsible for maintenance of cartilage.

Osteoarthritis is the degeneration of cartilage and other tissues in joints and is the most common form of arthritis in Australia, with one in five people over the age of 45 having the condition. Often described as a 'wear and tear' condition, factors such as ageing, obesity, injury, and family history contribute to the progression of osteoarthritis. Researchers have discovered a novel population of stem cells - marked by the Gremlin 1 protein - responsible for the progression of osteoarthritis. Treatment with fibroblast growth factor 18 (FGF18) stimulated the proliferation of Gremlin 1 cells in joint cartilage in mice, leading to significant recovery of cartilage thickness and reduced osteoarthritis.

Gremlin 1 cells present opportunities for cartilage regeneration and their discovery will have relevance to other forms of cartilage injury and disease, which are notoriously challenging to repair and treat. It challenges the categorisation of osteoarthritis as wear and tear. "With this new information, we are now able to explore pharmaceutical options to directly target the stem cell population that is responsible for the development of articular cartilage and progression of osteoarthritis."

Though this discovery is limited to animal models, there are genetic similarities to human samples, and human trials are ongoing. Results of a five-year clinical trial study using FGF18, known clinically as Sprifermin, were published in 2021 with potential long-term clinical benefit and no safety concerns. Phase 3 of the Sprifermin trial is ongoing, and researchers envision public access to this treatment soon.

Link: https://www.eurekalert.org/news-releases/1006425

Many aspects of aging are correlated with one another. A simple model of aging as a collection of end results that are produced by the accumulation of forms of biochemical damage to cells and tissues would suggest that all age-related conditions will be at much the same stage in a given individual: it is all a matter of how much damage that individual accumulates over time. Aging isn't that simple, however. While it still arises from comparatively simple root causes, the aforementioned biochemical damage to cells and tissues, each specific consequence of that damage sits within a complicated, interacting network of cause and effect. A consequence can interact with its cause, and with other consequences, and with downstream effects that it causes itself, making them worse, or accelerating their progression. There is plenty of opportunity for feedback loops to form and for specific narrow aspects of aging to race ahead of others in any given individual, or for some parts of this network and consequent age-related conditions to be tightly coupled to one another versus loosely coupled to one another.

So when we ask why grip strength in older people appears to be correlated with working memory, one can start with the idea that perhaps the nervous system is subject to damage that degrades all of its capacities, whether in the memory systems of the brain, or in the innervation and control of muscles. Or perhaps chronic inflammation affects muscle tissue maintenance and the neurogenesis needed for memory through similar effects on the function of stem cell populations in muscle and brain. Or there could be many other reasons why these two aspects of aging are more tightly coupled to one another. In today's open access paper, researchers dig in to specific workings of the brain and muscle in their consideration of the correlation between aging of these two portions of physical function.

Does muscle strength predict working memory? A cross-sectional fNIRS study in older adults

This study investigated the correlation among muscle strength, working memory (WM), and cortical hemodynamics during the N-back task of memory performance, and further explored whether cortical hemodynamics during N-back task mediated the relationship between muscle strength and WM performance. We observed that muscle strength (particularly grip strength) predicted WM of older adults in this cross-sectional study, which validated our hypothesis and expanded on previous research findings. Studies demonstrated that grip strength predicted executive function decline in patients with mild cognitive impairment. Other cross-sectional studies showed that grip strength and lower limb strength also predicted cognitive impairment. Previous research revealed that grip strength was positively linked to cognitive functions such as WM, language fluency, and word recall.

The reason why grip strength predicted working memory might be the control of muscles by the nervous system. Grip strength was influenced not only by muscle volume but also by the central nervous system, conversely, neurologic deterioration not only contributed to cognitive decline but might also be a factor in strength loss. This was consistent with the findings of the present study, where we found that greater muscle strength was associated with higher levels of activation in specific regions of the prefrontal cortex (PFC)/a> and better WM performance. The greater the muscle strength, the stronger the activity of the left dorsolateral prefrontal cortex (L-DLPFC) at a low WM load (i.e., 0-back). At moderate, high WM load (i.e., 1-, 2-back), the greater the muscle strength, the more active areas - additionally right dorsolateral prefrontal cortex (R-DLPFC), right frontopolar area (R-FPA), and left frontopolar area (L-FPA). Some studies suggested that the PFC played a crucial role in high grip strength performance, indicating that it may be the connection between grip strength and executive function. A systematic review found that resistance exercise improved brain function, particularly changes in the PFC, accompanied by improvements in executive function. Our findings further validated that a certain level of muscle strength was beneficial for brain health.

Furthermore, our finding that higher WM load was associated with fewer activation areas supported our hypothesis and was consistent with the compensation-related utilization of the neural circuit hypothesis, which suggested that older adults showed over-activations at a lower WM load, and under-activations at a higher WM load. Previous research found that higher levels of oxyhemoglobin concentration in the PFC of older adults during cognitive tasks were associated with better cognitive performance, particularly in the DLPFC, which was closely linked to WM. Additionally, studies showed that the level of PFC activation increased with increasing WM load in older adults, and then tended to stabilize or decrease. Older adults exhibited greater DLPFC activation than younger adults during WM tasks, and meta-analysis showed that when young people and older adults had the same cognitive performance, young people exhibited greater activity in left ventrolateral prefrontal cortex (L-VLPFC), while older people exhibited greater activity in L-DLPFC. These findings suggested that older adults could compensate for cognitive performance by activating more task-related brain regions, supporting the assumption of a positive neurobiobehavioral relationship between cortical hemodynamics and cognitive performance.

However, our study found cortical hemodynamics during N-back tasks did not mediate the relationship between muscle strength and WM performance. It can be inferred that an increase in muscle strength was associated with prefrontal cortex activation, thereby promoting positive effects on brain health.

Some animals, even mammals such as the naked mole-rat, show few signs of degenerative aging across a life span, a state known as negligible senescence. Such species typically live considerably longer than their more evidently aging near relative species. There isn't any one path to negligible senescence, as demonstrated by the wide variety of ecological niches containing species found to be negligibly senescence. Can we learn from their biochemistry to find ways to meaningfully extend the healthy human life span? Undoubtedly so in the very long term, at the point at which the cutting edge of research is building entirely new higher animal genomes with confidence, but it is too soon to say whether any of the novel age-slowing and age-reversing therapies of the next few decades will be informed by an improved understanding of the comparative biology of aging.

Theoreticians in the 1960s who were trying to wrap their heads around the principles of why and how animals on this planet age argued that senescence is "inevitable." As time goes by, organisms grow old, and their probability of dying increases. But research into a wide range of organisms suggests this almost definitely isn't the case: there's a growing variety in how creatures grow old. On all branches of the evolutionary tree, some animals live fast and die young and those that are so old we don't even know how to measure their age.

Female sand-burrowing mayflies have about five minutes to two hours to mate before they die. Giant Sunda rats live about half a year, while the Rougheye rockfish can live over 200. While many evolutionary principles behind this baffling discrepancy have started to surface, the molecular and biological reasons for aging - and why different animals do it at different rates - still baffles scientists daily. From an evolutionary perspective, however, it is possible to retroactively notice some patterns about what factors might have put these animals in their position on the spectrum.

In general, the bigger you are, the harder it is for another animal to kill and eat you. This is one of the hypotheses for why animals like the bowhead whale - the longest-lived mammal on the planet, sometimes reaching ages of up to 200 years - lives for so long: they don't have many predators out to get them. Elephants also live long for similar reasons, and the size factor would also explain why animals like mice, rats, and voles are so short-lived. They're an easier snack. Bats, though, are tiny, yet one of the longest-lived mammals, too - reaching 40 years old. From an evolutionary perspective, it doesn't matter that they're so tiny, because they're still really good at escaping predators.

There's some evidence that Greenland sharks can live up to 500 years, as can the ocean quahog. They live in extremely icy Arctic ocean environments, which is often associated with slow metabolism and maturation and correlates with living longer. Animals living and evolving in environments that allow them to escape mortality also easily preserve their longevity. Take the Galapagos tortoise. They live on an island and don't have natural predators, so they can take longer to reproduce and grow older - even past 150. Animals with the longest lifespans are often characterized by unique adaptations, habitat, and evolutionary factors that allow them to live for extended periods.

Link: https://www.discovermagazine.com/the-sciences/negligible-senescence-why-do-some-animals-age-differently

Senescent cells accumulate with age throughout the body. In youth the immune system promptly removes senescent cells, but this clearance slows with advancing age, leading to a growing population of lingering senescent cells. Senescent cells cease replicating and devote their efforts to the production of pro-growth, pro-inflammatory signals that become disruptive to tissue structure and function. Thus a population of senescent cells acts to actively maintain a degraded state of tissue, and their removal is immediately beneficial. Mouse studies show compelling, rapid reversals of age-related disease and extended life span resulting from the use of senolytic therapies to clear senescent cells. Of note, metabolic diseases associated with obesity, and which become worse with old age, appear involve senescent cells in a prominent role. One of the reasons that obesity is bad for health is that it accelerates the accumulation of senescent cells.

Cellular senescence refers to a stable non-proliferative state that cells enter in response to various stresses. This process is implicated in the development of various age-related diseases, including body aging, tumors, and senile dementia. Recently, an increasing number of researchers have focused on the relationship between cellular senescence and metabolic disorders. First, key cells involved in metabolic regulation undergo age-related changes. In patients with diabetes, the proportion of aging β-cells in the pancreas increases, and eliminating these cells can effectively prevent the onset and development of diabetes. In adipose tissue, aging adipose precursor cells promote insulin resistance in adipose cells. In addition, aging endothelial cells contribute to the formation of atherosclerotic plaques and increase plaque instability.

Second, the secretory phenotype of senescent cells undergoes significant changes, resulting in the production of a variety of pro-inflammatory factors. This phenomenon is referred to as the Senescence-Associated Secretory Phenotype (SASP). As a result, the continued accumulation of senescent cells can cause chronic inflammation. This chronic inflammatory response is considered as an important contributor to metabolic diseases. Thus, senescent cells may contribute to the onset and development of metabolic diseases, including diabetes, in various ways.

Aging intervention therapies targeting the clearance of senescent cells via senolytics or the modulation of their SASP via senomorphics have increasingly attracted the attention of researchers investigating their potential role in metabolic diseases. This paper reviews the relationship between metabolic diseases and cellular senescence and discusses the role of cellular senescence in these disorders, thereby providing new insights into their treatment.

Link: https://doi.org/10.3389/fcell.2023.1276707

Senescent cells accumulate with age, most likely largely due to the growing incapacity of the aging immune system, slowing the pace of removal of senescent cells to the point at which their numbers grow. Senescent cells cause significant harm via their pro-growth, pro-inflammatory signaling, disrupting tissue structure and function. Senolytic drugs can selectively destroy senescent cells, largely by attacking mechanisms that provide resistance to the programmed cell death process of apoptosis, but a range of other approaches are under development. First generation senolytics have performed impressively in mouse models of a great many age-related conditions, rapidly reversing pathology and markers of age, and extending healthy life span. This makes their further development and availability in the clinic a matter of great interest.

Today's paper summarizes views on the development of senolytic drugs from a small panel of healthcare and pharmaceutical industry experts. The specific focus is the treatment of vascular disorders of aging, but the views are broadly applicable to the application of senolytic therapies to any age-related condition. I think the most interesting of their points of agreement is that there is a near complete lack of awareness of senolytics in the world at large. Many more clinical trials should be underway using the low cost senolytic combination of dasatinib and quercetin in terms of proving that it can work and finding useful human dosing strategies. It is entirely possible that most common age-related conditions don't have to be as severe as they are for the patients suffering them, but at the present pace it'll be years yet before any useful body of data emerges for that presently available senolytic therapy.

Exploring the perspectives of pharmaceutical experts and healthcare practitioners on senolytic drugs for vascular aging-related disorder: a qualitative study

The field of targeting cellular senescence with drug candidates to address age-related comorbidities has witnessed a notable surge of interest and research and development. This study aimed to gather valuable insights from pharmaceutical experts and healthcare practitioners regarding the potential and challenges of translating senolytic drugs for treatment of vascular aging-related disorders. This study employed a qualitative approach by conducting in-depth interviews with healthcare practitioners and pharmaceutical experts. Participants were selected through purposeful sampling. Thematic analysis was used to identify themes from the interview transcripts. A total of six individuals were interviewed, with three being pharmaceutical experts and the remaining three healthcare practitioners.

Health providers and pharmaceutical experts viewed that there are certain challenges and considerations associated with measuring outcomes and assessing the effects of senolytic therapies. One of the primary issues is that measurable outcomes may not be immediate. Senescent cell clearance and subsequent tissue regeneration may take time to manifest noticeable effects. More importantly, to date there are no tools such as imaging probes or biomarkers that can measure the clearance of senescent cells from tissue. The lack of such simple tools not only hamper the identification of senolytic drugs which are truly specific for senescent cells but also for monitoring therapeutic efficacy.

Results from completed trials of dasatinib and quercetin using intermittent dosing (i.e., consecutive treatment for 2-3 days with 2-week resting period) appears to be tolerable, with mild to modest adverse effects. Hence, it is crucial to establish the safety profile and dosing regimen of new senolytic drugs to harness the beneficial effects whilst minimizing risks. From the healthcare practitioners' perspective, it is crucial to ensure that the new senolytic therapy does not interact with other medications, particularly for elderly individuals who are already managing multiple conditions and taking numerous medications. While drug interaction profiles may be available for repurposed drugs, it may not the case for newly developed senolytics. To this end, potential drug-drug interactions, particularly with medications taken by the elderly individuals for their comorbidities have yet to be examined in preclinical and clinical studies and warrant future investigations. In this regard, pharmaceutical experts of this study pointed out the importance of addressing both the selectivity and specificity of senolytics. Improving senolytics selectivity for senescent cells while sparring healthy non-senescent cells is crucial to minimize potential side effects.

The pharmaceutical sector demonstrates a positive inclination towards the commercialization of new senolytic drugs, albeit with concerns around safety and efficacy. Besides sharing the same outcome-related concerns as with the pharmaceutical experts, healthcare practitioners anticipated a lack of awareness among the general public regarding the concept of targeting cellular senescence to delay vascular aging-related disorders, and this knowledge gap extends to healthcare practitioner themselves as well.

This review paper lumps together thoughts on the prospects for both epigenetic reprogramming and upregulation of autophagy as approaches to the treatment of Alzheimer's disease, the former a much more recent development in the research community, and the latter a long-running goal that has seen less concrete progress than desired. The long, slow path to any sort of success in the development of Alzheimer's therapies based on clearance of amyloid-β has led to considerable pressure to try other other avenues, but despite numerous trials and development programs, few of those have made much progress towards the clinic as of yet.

Age remains the largest risk factor in the development of neurodegenerative diseases such as Alzheimer's disease (AD). Numerous cellular hallmarks of aging contribute to the advancement of the pathologies associated with neurodegenerative disease. Not all cellular hallmarks of aging are independent and several fall into the broader category of cellular rejuvenation, which captures returning cells to a more youthful, improved functional state. Cellular rejuvenation is quickly becoming a hot topic in the development of novel therapeutic modalities for a range of diseases. Therapeutic approaches utilizing cellular rejuvenation technologies are rapidly advancing and will represent the next phase of AD therapeutics.

This review focuses on two important processes, epigenetic reprogramming, and chaperone-mediated autophagy (CMA) that play a critical role in aging and in neurodegenerative diseases and the potential therapeutic approaches (gene therapy, small molecule) towards targeting these mechanisms. In aging and in AD, epigenetic changes on DNA (e.g., hypermethylation on CpG islands) lead to alterations in gene expression. Partial epigenetic reprogramming utilizes transcription factors to remove the epigenetic marks and to rejuvenate cells to a more youthful state. During aging and in neurodegenerative disorders, CMA becomes impaired resulting in a buildup of proteins known to be associated with neurodegenerative pathologies. The protein buildups lead to aggregates that preclude proteostasis leading to cell toxicity. Small-molecule CMA activators restore proteostasis and limit toxicity enabling cellular rejuvenation.

Link: https://doi.org/10.14283/jpad.2023.106

Few mammalian species exhibit menopause. It is thought that humans evolved into this state of post-reproductive old age in part because older individuals can help to enhance the reproductive fitness of their direct offspring. This view is known as the "grandmother hypothesis". The same behavior is observed in orcas, one of the few other mammals to exhibit menopause. Researchers here provide evidence for chimpanzees to undergo menopause, which is a strike against the grandmother hypothesis, as chimpanzee elders do not assist their offspring in this way.

A team of researchers studying the Ngogo community of wild chimpanzees in western Uganda's Kibale National Park for two decades has published a report showing that females in this population can experience menopause and postreproductive survival. Prior to the study these traits had only been found among mammals in a few species of toothed whales, and among primates only in humans. These new demographic and physiological data can help researchers better understand why menopause and post-fertile survival occur in nature, and how it evolved in the human species.

The grandmother hypothesis has been used to explain the existence of human postmenopausal survival, proposes that females in their postreproductive years may be able to pass on more of their genes by helping to raise the birth rates of their own children or by caring directly for grandchildren, thereby increasing grandchildren's odds of survival. And indeed, several studies of human grandmothers have found these positive effects. But chimpanzees have very different living arrangements than humans. Older female chimpanzees typically do not live near their daughters or provide care for grandchildren, yet females at Ngogo often live past their childbearing years.

While substantial postreproductive life spans have not previously been observed in other long-term studies of wild chimpanzees, they have sometimes been seen in chimpanzees and other primates in captivity, who receive good nutrition and medical care. This raises the possibility that the postreproductive life spans of female Ngogo chimpanzees may be a temporary response to unusually favorable ecological conditions, as this population enjoys a stable and abundant food supply and low levels of predation. Another possibility, however, is that postreproductive life spans are actually an evolved, species-typical trait in chimpanzees but have not been observed in other chimpanzee populations because of the recent negative impacts of humans.

Link: https://newsroom.ucla.edu/releases/ucla-researcher-first-proof-menopause-wild-chimpanzees

Epigenetic patterns determine the behavior of a cell, and change constantly in response to cell state and the surrounding tissue environment. Epigenetic state can be used to measure biological age, the epigenetic clock. When an epigenetic clock indicates an age older than chronological age, that is referred to as epigenetic age acceleration. While the clocks are not fully understood in detail, it is thought that the specific epigenetic changes measured are reflective of the burden of cell and tissue damage and dysfunction that causes aging. This acceleration has been shown to correlate with risk and status of a number of age-related conditions.

In today's open access paper, researchers compare epigenetic age acceleration with cardiovascular risk factors. Their point of view is that epigenetic aging, and specifically increased DNA methylation, is a cause rather than a consequence of dysfunction. The work on epigenetic reprogramming of the past few years is supportive of this view that epigenetic change produces significant downstream consequences in aging: reprogramming the epigenetics of old cells does appear to produce some degree of rejuvenation in cells, tissues, and animals. It may be quite close to the root causes of aging, if the work showing it to be a direct consequence of DNA double strand break repair continues to hold up. This is not supportive of the idea that increased DNA methylation is generally a bad thing, however, or that blanket reductions in DNA methylation will be a good basis for therapy.

Accelerated DNA methylation age plays a role in the impact of cardiovascular risk factors on the human heart

DNA methylation (DNAm) age acceleration (AgeAccel) and cardiac age by 12-lead advanced electrocardiography (A-ECG) are promising biomarkers of biological and cardiac aging, respectively. We aimed to explore the relationships between DNAm age and A-ECG heart age and to understand the extent to which DNAm AgeAccel relates to cardiovascular (CV) risk factors in a British birth cohort from 1946.

We studied four DNAm ages (AgeHannum, AgeHorvath, PhenoAge, and GrimAge) and their corresponding AgeAccel. Outcomes were the results from two publicly available ECG-based cardiac age scores: a Bayesian A-ECG-based heart age score and a deep neural network (DNN) ECG-based heart age score. DNAm AgeAccel was also studied relative to results from two logistic regression-based A-ECG disease scores, one for left ventricular (LV) systolic dysfunction (LVSD), and one for LV electrical remodeling (LVER). Generalized linear models were used to explore the extent to which any associations between biological cardiometabolic risk factors (body mass index, hypertension, diabetes, high cholesterol, previous cardiovascular disease [CVD], and any CV risk factor) and the ECG-based outcomes are mediated by DNAm AgeAccel.

By the age of 60, participants with accelerated DNA methylation appear to have older, weaker, and more electrically impaired hearts. We show that the harmful effects of CV risk factors on cardiac age and health, appear to be partially mediated by DNAm AgeAccelPheno and AgeAccelGrim. This highlights the need to further investigate the potential cardioprotective effects of selective DNA methyltransferases modulators.

Cholinergic neurons are important in many functions in the brain. It is becoming apparent that chronic inflammation in brain tissue is an important contributing cause in the decline of cholinergic systems of brain function. Microglia, innate immune cells of the brain, are one of the cell populations responsible for sustaining harmful inflammation. These cells become active and inflammatory in ever increasing numbers in the aging brain, a maladaptive reaction to growing levels of metabolic waste and pro-inflammatory signaling outside cells, alongside age-related dysfunction inside cells.

This study assessed the effect of normal aging and neuroinflammation on the medial septal Iba-1+ microglia population and the consequential effect on the choline acetyl transferase (ChAT)+ cholinergic cell population. Chronic IL-6 expression in the mouse brain significantly increased the reactive Iba-1+ microglia and decreased the ChAT+ cholinergic cell number in the medial septum and this tendency exacerbated with aging. We also showed that aging and chronic IL-6 expression reorientated the septal microglia morphology towards a more reactive and de-ramified pro-inflammatory phenotype.

These findings further reflected upon the septal cholinergic cell population displaying a neurodegenerative phenotype. The resultant direct effect of neuroinflammation and aging on the septal cholinergic population mirrored upon the hippocampal pyramidal cell dendritic spine density. Overall, these findings demonstrate a potential detrimental effect of chronic microglia activation on the medial septum, which can exacerbate throughout aging, leading to cholinergic dysfunction that could in turn disrupt hippocampal pyramidal cell network regulation.

Link: https://doi.org/10.1186/s12974-023-02897-5

Anabolic resistance is a description of a state, not a starting point for a therapy. Anabolism is the metabolism of growth and repair, and in a state of anabolic resistance cells become less responsive to the signaling environment that normally encourages growth and repair. If the goal is therapies, then why this anabolic resistance occurs becomes the question. Muscles lose mass and strength with age, leading to the condition called sarcopenia. This, obviously, must involve anabolic resistance, and here researchers discuss what is known of this view of the sarcopenia of old age.

The development of sarcopenia in the elderly is associated with many potential factors and/or processes that impair the renovation and maintenance of skeletal muscle mass and strength as ageing progresses. Among them, a defect by skeletal muscle to respond to anabolic stimuli is to be considered. Common anabolic stimuli/signals in skeletal muscle are hormones (insulin, growth hormones, IGF-1, androgens, and β-agonists such epinephrine), substrates (amino acids such as protein precursors on top, but also glucose and fat, as source of energy), metabolites (such as β-agonists and HMB), various biochemical/intracellular mediators), physical exercise, neurogenic and immune-modulating factors, etc. Each of them may exhibit a reduced effect upon skeletal muscle in ageing.

In this article, we overview the role of anabolic signals on muscle metabolism, as well as currently available evidence of resistance, at the skeletal muscle level, to anabolic factors, from both in vitro and in vivo studies. Some indications on how to augment the effects of anabolic signals on skeletal muscle are provided.

Link: https://doi.org/10.3390/nu15184073

While reprogramming usually refers to the production of pluripotent stem cells from somatic cells, is is becoming more broadly used to describe a range of manipulations in which the characteristics of cells in aged tissues are rejuvenated in some way. For example, finding small molecule drug candidates that can restore the potency of aging stem cell populations is the topic of today's open access paper. Since the regulation of adult stem cell and progenitor cell state is complex, there are likely many ways in which it can be manipulated, and those ways probably differ by stem cell type.

Researchers here describe the production of a system for evaluation of stem cell state and discovery of new small molecules to alter that state. They applied this system to aging tendon stem cells, and came up with a drug candidate that restores the regenerative capacity of tendons in old animals. One can make the case for this to be a form of reprogramming because of the way in which tendon stem cells lose their stemness with age; in other stem cell populations, loss of capacity with age may occur for different reasons, such as greater quiescence, or reduced population size, and different solutions will be needed.

Prim-O-glucosylcimifugin ameliorates aging-impaired endogenous tendon regeneration by rejuvenating senescent tendon stem/progenitor cells

Like most tissue regenerative processes, the regenerative capacity of tendons decreases with aging or even fails and is often accompanied by stem cell exhaustion and cellular senescence. The regenerative capacity of adult tendons depends on the status of stem/progenitor cells (TSPCs), which can activate and expand to form new tendon collagen fibers or self-renew to restore the TSPC pool in response to tissue damage. At later stages in life, TSPCs present a marked impairment of stemness and regenerative capacity, resulting in inefficient tendon self-repair. In previous research, we found that the difference in TSPC stemness between the neonatal and adult stages influenced multiple biological functions of TSPCs and the adult tendon regenerative process.

In this context, a reasonable stemness-modulating method is a prospective strategy for remedying aged TSPCs. Traditionally, the dampened stemness can only be reversed by inducing Yamanaka factors genetically. However, an efficient strategy to identify stemness-promoting small molecules is currently lacking. In recent years, deep learning approaches have been widely applied in target-based drug design and for the development of various therapeutic strategies. However, these methods cannot be used when the target is unknown; for instance, with regard to stemness promotion, only four transcription factors are known. In this study, we employed the newly developed system, DLEPS, which is an efficacy prediction system using transcriptional profiles with deep learning, to identify potential drugs to stimulate stemness.

In our study, we found that the top-ranked candidate compound prim-O-glucosylcimifugin (POG) could efficiently inhibit TSPC senescence and promote their tenogenic differentiation potential in an in vitro serial passaging cell senescence model. We also found that the top-ranked POG potently rejuvenated the proliferation and tenogenic potential of TSPCs from both aged rats and middle-aged humans by maintaining stemness and suppressing senescence.

Generally, the results from multiple senescent cell models provide solid and convincing evidence that POG is indeed a potent antisenescent drug for TSPCs. Moreover, the systemic administration of POG and the local delivery of POG encapsulated in nanoparticles were found to promote aged tendon self-repair in small-sized, partial transection tendon injuries. The combination of POG administration and the transplantation of scaffolds significantly enhanced the aged endogenous regenerative capacity in large-sized, full-cut tendon window defects in aged rats. These findings provide multiple alternative strategies for endogenous tendon repair and regeneration in aging according to different injury conditions.

As researchers here point out, cytotoxic T cells can in principle attack and destroy lingering senescent cells in aged tissues. That they don't do enough of this in old age is clear, but that they are capable of it at all opens the door to finding ways to encourage greater activity. Deciduous Therapeutics runs a development program focused on encouraging a different set of immune cells to kill senescent cells, while engineered T cells equipped with chimeric antigen receptors have been tested in animal models for their ability to kill senescent cells. It is likely that other groups will try a variety of senolytic immunotherapy approaches in the years ahead.

With their continuous production of the senescence-associated secretory phenotype (SASP), senescent cells (SnCs) hinder tissue renewal and accelerate pathological deterioration, thus damaging the development and maintenance of functional ability, which is the major concern of healthy aging. The immune system primarily takes the responsibility of identifying and recycling irregular cells, thus ensuring an endogenous approach to achieve healthy aging. However, the immunosurveillance function gradually loses its balance with cellular and microenvironmental changes in the aging process, indulging the irreversible aging process. Hence, the restoration and mobilization of immunosurveillance could be an entry point to boost healthy aging.

Cytotoxic T lymphocytes (CTLs), as an important part of the immune system, mainly include CD4+ CTLs, CD8+ CTLs, and artificially modified cytotoxic chimeric antigen receptor T cells (CAR T cells). CTLs bind with antigen-presenting target cells, releasing perforin and granzyme which induce the death of target cells. Studies have suggested the well-established role of CTLs in eliminating cancer cells selectively. Could this theory be applied to the elimination of SnCs effectively? p21, a classical marker of cellular senescence, was found to induce CXCL14 and other immune-modulatory factors expression in hepatocytes. These immune modulatory factors further boosted M1 macrophage differentiation and the recruitment of CTLs to p21-expressing hepatocytes, strongly suggesting that CTLs may contribute to the immune clearance of SnCs

Immunosurveillance on aging is a complex yet poorly understood natural process. Revealing attempts have been made to identify prominent senescent hallmarks that activate CTLs. Furthermore, the demonstration of how SnCs are eliminated by CTLs in natural processes offers potential interference approaches. The exploratory application of immune checkpoint blockade and CAR T cells provides strategies to prevent SnCs from escaping immunosurveillance. With the discovery of new aging hallmarks and successful mobilization of CTLs, future senolysis may contribute to healthy aging and prevent aging-related diseases.

Link: https://doi.org/10.1038/s41420-023-01699-1

Senescent cells of many types accumulate in tissues throughout the body with age due to an imbalance between the pace of creation and pace of destruction, the immune system progressively losing its ability to destroy these senescent cells in a timely manner. Senescent cells cease to replicate and secrete a potent mix of pro-inflammatory signals, harmful to surrounding tissue when sustained over the long term. Here, researchers note one of the many specific ways in which senescent cells can impair function; this one example is multiplied a thousand times across locations, tissue types, and cell types throughout the aging body.

Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype.

We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.

Link: https://doi.org/10.15252/emmm.202317907