Fight Aging! Newsletter, February 19th 2024

Osteoporosis is characterized by low bone mass and destroyed microarchitecture, resulting in an increased risk of fracture. Additionally, decreased bone regenerative potential and a high risk of impaired or incomplete fracture healing in elderly individuals contribute to long-term disability or even death. However, the etiology of age-related impaired skeletal regenerative capacity remains incompletely understood.

Aged-related skeletal deterioration and impaired fracture healing are related to the accumulation of senescent cells, which are characterized by permanent cell cycle arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). Our previous study found that senescent immune cells accumulated in the bone marrow and secreted grancalcin (GCA), which suppressed bone turnover and promoted marrow fat accumulation. Thus, accumulated senescent cells in the bone microenvironment play a significant role in skeletal aging, and eliminating senescent cells and/or blunting their SASP factors can prevent or delay age-related bone loss. Recent studies also suggested that the accumulation of senescent cells impaired fracture healing, and removing senescent cells by genetic and pharmacological approaches in aged mice improved fracture repair. However, the effects and underlying mechanisms of senescent cells in fracture healing during aging remain elusive.

In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers skeletal stem cell and progenitor cell (SSPC) senescence and impairs fracture healing. Local injection of human recombinant GCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for incomplete fracture healing in elderly individuals.

Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18,400 unique articles, resulting in 19 included studies.

Rapamycin and its derivatives improved the immune, cardiovascular, and integumentary systems in healthy individuals or individuals with ageing-related diseases. Overall, these drugs had no significant effects on the endocrine, muscular, or neurological systems. The effects of rapamycin or its derivatives on the respiratory, digestive, renal, and reproductive systems were not assessed. There was no clear relationship between the dose of rapamycin or its derivatives and the effects of these drugs on different physiological systems. No serious adverse events were attributed to the interventions.

Although studies have reported that rapamycin and its derivatives can enhance learning and memory, and reduce neurodegeneration in animal models, these effects were not observed in the human studies assessed in this systematic review. Moreover, the reported effects on ageing-related macular changes were inconsistent. For instance, rapamycin reduced the need for anti-VEGF usage but also led to the loss of visual acuity in individuals with geographic atrophy in age-related macular degeneration. In addition, in preclinical studies, pharmacological mTOR inhibition reduced age-related cardiac inflammation, fibrosis, hypertrophy, and systolic dysfunction. Although improvements in the cardiac index and reductions in both pulmonary vascular resistance and pulmonary arterial pressure have been observed following intervention with everolimus, the effects of rapamycin and its derivatives on cardiovascular parameters in humans should be assessed more comprehensively in future studies.

As individuals age, their glucose tolerance declines. Overactivation of the mTOR pathway leads to the activation of S6K-1 and phosphorylated IRS-1, impairing the stimulation of PI3K by insulin and, subsequently, lowering insulin resistance in human muscle. The effects of rapamycin on glucose metabolism differed by study setting. Although rapamycin treatment increased glucose turnover under conditions of induced peripheral hyperinsulinaemia, it did not affect glucose turnover when there was low peripheral insulin, and did not affect post-exercise insulin concentrations, or post-amino acid infusion fasting insulin, C-peptide, glucose, or glucagon concentrations.

mTOR is hypothesised to be a crucial regulator responsible for maintaining skeletal muscle mass. Although animal studies investigating mTOR inhibition by rapamycin and its derivatives on the muscular system have reported inconsistent results, the human studies we assessed reported no significant effects. However, in these studies, rapamycin was administered in single doses. Further research with different dosing regimens might be necessary to better understand the potential effects of rapamycin and its derivatives on the muscular system.

Topical rapamycin significantly reduced the expression of markers of skin ageing. However, the effects of systemically administered rapamycin or its derivatives on the skin were not investigated and, therefore, require further research.

As individuals age, their capacity to mount a robust immune response diminishes, rendering them more vulnerable to infections and poor response to vaccinations. The mTOR pathway is a crucial signalling pathway within the immune system, controlling the activation, proliferation, differentiation, and function of immune cells. Although rapamycin is known to be immunosuppressive, there are several mechanisms that might explain the immunostimulatory effect of rapamycin in vitro and in animal studies, such as the improvement of immune memory, alteration of CD8+ cell response, and promotion of regulatory T-cell survival and function. In the studies analysed in this review, rapamycin and its derivatives improved immune function mainly by altering adaptive immunity.

There was no clear relationship between the dose of rapamycin or its derivatives and the efficacy of these drugs in ameliorating ageing-related outcomes in the assessed studies. This finding suggests that even though the pharmacokinetics of rapamycin are well known, pharmacodynamic studies that focus on target (ie, mTOR) engagement and the effects of rapamycin on ageing-related biomarkers are needed to establish an adequate dosing regimen for geroprotection.

One of the body systems profoundly affected by aging is the skeletal system, giving rise to conditions such as osteoporosis and osteoarthritis that become increasingly prevalent with age. Additionally, there is a notable upswing in the incidence of bone fractures, which is associated with higher rates of morbidity and mortality. Among these fractures, hip fractures (HF) stand out as particularly concerning due to their severe consequences. HF not only leads to chronic pain and disability but also entails a high morbidity risk, an increased susceptibility to major depression, and a loss of autonomy, and often necessitates institutionalization for individuals who were previously independent.

Peripheral blood monocytes, a heterogeneous population comprising approximately 10% of peripheral leukocytes in humans, play a pivotal role in both innate and adaptive immunity. They function as phagocytic cells, eliminating pathogens, and also produce cytokines. Understanding the roles and mechanisms of macrophages, which monocytes can differentiate into, in the context of fractures, may provide valuable insights into predicting the timing of surgery for HF patients and mitigating the immunosuppressive effects that contribute to mortality.

A notable change in older adults is the increased expression of activation, adhesion, and migration markers in circulating monocytes. However, there is a decrease in the expression of co-inhibitory molecules. Recently, research evidence has shown that the migration of specific monocyte subsets to the site of hip fracture plays a crucial role in bone resorption and remodeling, especially concerning age-related factors. In this review, we summarize the current knowledge about uniqueness characteristics of monocytes, and their potential regulation and moderation to enhance the healing process of hip fractures. This breakthrough could significantly contribute to the comprehension of aging process at a fundamental aging mechanism through this initiative would represent a crucial stride for diagnosing and treating age related hip fracture.

Handgrip strength (HGS), which represents global muscle strength, is a powerful indicator of disability and mortality in older adults; it is also used for the diagnosis of possible or probable sarcopenia and physical frailty. This study aimed to explore the metabolic mechanisms and potential biomarkers associated with declining HGS among older adults. We recruited 15 age- and environment-matched inpatients (age, 77-90 years) with low or normal HGS. Liquid chromatography-mass spectrometry (LC-MS) and 16S ribosomal DNA (rDNA) gene sequencing were performed to analyze the metabolome of serum and stool samples and the gut microbiome composition of stool samples. Spearman's correlation analysis was used to identify the potential serum and fecal metabolites associated with HGS.

We assessed the levels of serum and fecal metabolites belonging to the class of cinnamic acids and derivatives and reported that the levels of carboxylic acids and their derivatives decreased in the low-HGS group. Serum levels of microbial metabolites, including cinnamoylglycine, 4-methoxycinnamic acid, and (e)-3,4,5-trimethoxycinnamic acid, were positively correlated with HGS. We found that gut microbial α-diversity was significantly higher in the low-HGS group, whereas higher β-diversity was observed in the normal group. The relative abundances of the genera Parabacteroides and Intestinibacter increased significantly in the low-HGS group and were negatively correlated with the serum levels of cinnamoylglycine. The identified metabolites whose levels were markedly altered, and intestinal flora associated with these metabolites suggest the potential metabolic underpinnings for HGS and provide a basis for the further identification of biomarkers of muscle strength decline in older adults.

The present study focused on the association of changes in waist circumference (WC), waist-to-height ratio (WHtR), and weight-adjusted-waist index (WWI) with multimorbidity among older Chinese adults. Our results showed that rising changes in WC, WHtR, and WWI were associated with an increased risk of multimorbidity. Compared with participants in the persistently low group of WC, WHtR, those in the gain group and the persistently high group of WC, WHtR had significantly higher multimorbidity risk. Moreover, compared with the persistently low WWI group, the WWI loss group was correlated with a lower risk of multimorbidity.

The association between adiposity and multimorbidity has been extensively explored in epidemiological studies. Although studies have consistently demonstrated that obesity is positively associated with multimorbidity, the studies on the relationship between obesity indicators change and multimorbidity are limited and still controversial.

In this study, we first explored the association between WC, WHtR, and WWI change patterns and multimorbidity. WC and WHtR are considered to be important anthropometric indicators of abdominal obesity. Previous studies have suggested that WC and WHtR can reflect body fat percentage accurately and play an important role in predicting some chronic diseases, such as cardiovascular disease and metabolic syndrome. The pathway may explain that abdominal obesity significantly increased plasma triglycerides, low density lipoproteins, and very low density lipoproteins, which have been shown to increase the risk of adverse outcomes such as cardiovascular disease, diabetes, hypertension, and kidney diseases. In addition, people with abdominal obesity tend to have excess visceral fat, which can lead to high doses of adipokines from the portal vein to the liver and other body tissues, causing a variety of chronic diseases. Previous studies have highlighted that visceral adipose tissue produces large amounts of interleukin-6 (IL-6), which promotes the secretion of acute-phase proteins such as C-reactive protein (CRP), and thus the levels of IL-6 and CRP are significantly increased in individuals with abdominal obesity.

Therefore, WWI loss may reduce inflammation and thus the risk of multimorbidity, which could reasonably explain our results. Moreover, the persistently low WWI group included those who had always been underweight, and underweight older adults were prone to malnutrition, which is associated with some noninfectious chronic diseases. This may explain why the risk of multimorbidity was higher in the persistently low WWI group than in the WWI loss group.

During the first senotherapeutics conference organized by the Phaedon Institute at the Buck Institute for Research on Aging, experts on the molecular and cellular mechanisms of aging, pathogenesis of age-related diseases, and drug discovery and development convened to delve into ideas on the past, present, and future of targeting senescent cells. A focal point of discussion revolved around the heterogeneity of cellular senescence, and its profound implications for the development of treatments. Presenters highlighted the diverse profiles of senescent cells, emphasizing differences in gene expression, secretory patterns, and functional roles, in addition to the importance of the tissue microenvironment.

Senescent cells represent a potential target for geroprotection and reduction of multimorbidity, but owing to current regulations, clinicians and pharmaceutical companies are focusing on the use of senotherapeutics for specific and selective age-related diseases. A Phase 2B trial sponsored by Unity Biotechnology is currently ongoing for the treatment of Diabetic Macular Edema (DME) using the senolytic agent UBX1325, which inhibits Bcl-XL. The Translational Geroscience Network runs a number of Phase 1 and Phase 2 trials using senolytic compounds, such as Dasatinib, Quercetin, and Fisetin, for the treatment of sepsis, chronic kidney disease, lung fibrosis, and Alzheimer's disease. Additionally, many other pathological conditions have been discussed as potential indications for the use of therapeutic compounds. For example, efforts are currently being made to selectively target senescent cell subtypes in pre-clinical models of skin and muscle dysfunctions with novel senolytic small molecules in development at Rubedo Life Sciences and Boehringer-Ingelheim, respectively.

While these represent pioneering studies and the opportunity to demonstrate the unequivocal pathological role of certain senescence subsets, challenges remain in the path to harnessing the therapeutic potential of targeting cellular senescence. Participants emphasized the need for a more comprehensive understanding of the dynamic nature of senescent cells, their role and localization in various tissues and tissue areas, and the need for more accurate and sensitive biomarkers. This discussion highlighted the importance of multi-laboratory and multi-center efforts in adapting the newest technologies with single-cell resolution for the identification and specification of senescent cells in vivo. These studies can offer novel targets for interventions and novel markers for a standardized evaluation of the efficacy of anti-senescence approaches in humans. Overall, the pleiotropic diversity and heterogeneity of cellular senescence invites the development of diverse strategies and modalities to target subsets of senescent cells according to their physiopathological roles. The ongoing effort in academic and industrial laboratories to develop different senotherapeutics is strategic to enable advancement in the clinic of multiple novel therapeutic opportunities, possibly in parallel.

The redox process and cellular senescence are involved in a range of essential physiological functions. However, they are also implicated in pathological processes underlying age-related neurodegenerative disorders, including Alzheimer's disease (AD). Elevated levels of reactive oxygen species (ROS) are generated as a result of abnormal accumulation of beta-amyloid peptide (Aβ), tau protein, and heme dyshomeostasis and is further aggravated by mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Excessive ROS damages vital cellular components such as proteins, DNA, and lipids. Such damage eventually leads to impaired neuronal function and cell death.

Heightened oxidative stress can also induce cellular senescence via activation of the senescence-associated secretory phenotype to further exacerbate inflammation and tissue dysfunction. In this review, we focus on how changes in the redox system and cellular senescence contribute to AD and how they are affected by perturbations in heme metabolism and mitochondrial function. While potential therapeutic strategies targeting such changes have received some attention, more research is necessary to bring them into clinical application.

The Hallmarks of Aging arose as an answer to the great amount of information generated by aging research, with the aim of creating a conceptual framework to integrate and organize the existing knowledge. The objective of the present review has been to determine the impact of the Hallmarks and address if the purpose that gave them rise was achieved. For that aim, we reviewed the literature that cited any of the two versions of the Hallmarks. The conclusion was that the first version (with the second one also following the same trend) accomplished the goal, as it influenced a vast variety of fields ranging from the different areas of aging research to other related fields. Furthermore, it also inspired other authors and served as a model for the organization of knowledge, giving rise to a wide variety of "Hallmarks" in other subjects.

Nevertheless, this impact was not unidirectional, since the research promoted by the first version of the Hallmarks generated a great deal of knowledge that gave rise to the updates included in the second version. This updated version included three new hallmarks and, in spite of its recent publication, it is being highly cited and has already influenced some studies and served as a knowledge-structuring model. Therefore, it can be concluded that the usefulness of The Hallmarks of Aging in aging-related research seems undeniable.

However, as any approximation it has its limitations and it should be carefully revised, considering the latest advances, to determine whether all the hallmarks are still valid and if it is necessary to include new ones. In this sense, this review has analyzed the possible emerging hallmarks that were not included in the second version and the ones that were included but as components of other hallmarks. Assuming that a conceptual framework must be as schematic and organized as possible and the still limited evidence supporting some of these candidate hallmarks, we conclude that further investigations are needed to assess if any of these proposed hallmarks should be included in the next version. Even though the current Hallmarks of Aging provide a valid scaffold for aging research, there is no doubt that, as knowledge advances, updated versions of the Hallmarks will become necessary.

The interplay between microbes and the skin barrier holds pivotal significance in skin health and aging. The skin and gut, both of which are critical immune and neuroendocrine system, harbor microbes that are kept in balance. Microbial shifts are seen with aging and may accelerate age-related skin changes. This comprehensive review investigates the intricate connection between microbe dynamics, skin barrier, and the aging process. The gut microbe plays essential roles in the human body, safeguarding the host, modulating metabolism, and shaping immunity.

Aging can perturb the gut microbiome which in turn accentuates inflammaging by further promoting senescent cell accumulation and compromising the host's immune response. Skin microbiota diligently upholds the epidermal barrier, adeptly fending off pathogens. The aging skin encompasses alterations in the stratum corneum structure and lipid content, which negatively impact the skin's barrier function with decreased moisture retention and increased vulnerability to infection. Efficacious restoration of the skin barrier and dysbiosis with strategic integration of acidic cleansers, emollients with optimal lipid composition, antioxidants, and judicious photoprotection may be a proactive approach to aging. Furthermore, modulation of the gut-skin axis through probiotics, prebiotics, and postbiotics emerges as a promising avenue to enhance skin health as studies have substantiated their efficacy in enhancing hydration, reducing wrinkles, and fortifying barrier integrity.

In summary, the intricate interplay between microbes and skin barrier function is intrinsically woven into the tapestry of aging. Sound understanding of these interactions, coupled with strategic interventions aimed at recalibrating the microbiota and barrier equilibrium, holds the potential to ameliorate skin aging. Further in-depth studies are necessary to better understand skin-aging and develop targeted strategies for successful aging.

Allostatic load (AL) refers to the activation of physiological regulatory systems in response to chronic stress and the long-term effects on the body and brain. AL reflects cumulative, multisystem physiological dysregulation, which is the result of repeated cycles over the lifespan in response to stressful life evens events. A literature review of AL and health reported that older and disadvantaged groups exhibited a higher risk of high AL. The primary mediators of AL include stress hormones and cytokines that influence the secondary outcomes of systematic dysregulation of metabolic, cardiovascular, and second-order inflammatory biomarkers over time.

Importantly, adults aged over 40 years old had a more than 2-fold higher risk of high AL than adults aged 18-29 years old. The effect of increased AL varies according to age, as well as multiple health-related and clinical factors. The aims of this study were to explore 1) the association of age and depressive symptoms with allostatic load and 2) whether socioeconomic (e.g., birth-assigned sex, educational level, marital status) and/or lifestyle factors (e.g., current smoking, high alcohol consumption, no physical exercise) are associated with high AL.

Thirteen biomarkers were used to construct AL. High AL was defined as scoring highly in ≥4 items. AL scores of 4 and above were exceeded in the age group of 45-54 years in men and 65-74 years in women. Age was the strongest predictor for belonging to the high AL score group. In addition, elevated depressive symptoms (BDI-6 ≥ 4), male sex, not engaging in physical exercise, high alcohol use, and a low level of education were associated with an increased likelihood of belonging to the high AL group.

Changes in DNA methylation with age are observed across the tree of life. The stereotypical nature of these changes can be modeled to produce epigenetic clocks capable of predicting chronological age with unprecedented accuracy. Despite the predictive ability of epigenetic clocks and their utility as biomarkers in clinical applications, the underlying processes that produce clock signals are not fully resolved, which limits their interpretability.

Here, we develop a computational approach to spatially resolve the within read variability or "disorder" in DNA methylation patterns and test if age-associated changes in DNA methylation disorder underlie signals comprising epigenetic clocks. We find that epigenetic clock loci are enriched in regions that both accumulate and lose disorder with age, suggesting a link between DNA methylation disorder and epigenetic clocks. We then develop epigenetic clocks that are based on regional disorder of DNA methylation patterns and compare their performance to other epigenetic clocks by investigating the influences of development, lifespan interventions, and cellular dedifferentiation.

We identify common responses as well as critical differences between canonical epigenetic clocks and those based on regional disorder, demonstrating a fundamental decoupling of epigenetic aging processes. Collectively, we identify key linkages between epigenetic disorder and epigenetic clocks and demonstrate the multifaceted nature of epigenetic aging in which stochastic processes occurring at non-random loci produce predictable outcomes.

While the innate immune response is the first line of defense against viruses, it can also respond to molecules the body makes that resemble pathogens - including misplaced mitochondrial DNA (mtDNA). This response can lead to chronic inflammation and contribute to human diseases and aging. Scientists have been working to uncover how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathways did not apply to all mtDNA stress conditions. Researchers turned to sophisticated imaging techniques to gather clues as to where and when things were going awry in those mitochondria.

The team discovered a process beginning with a malfunction in mtDNA replication that caused mtDNA-containing protein masses called nucleoids to pile up inside of mitochondria. Noticing this malfunction, the cell then begins to remove the replication-halting nucleoids by transporting them to endosomes, a collection of organelles that sort and send cellular material for permanent removal. The endosome gets overloaded with these nucleoids, springs a leak, and mtDNA is suddenly loose in the cell. The cell flags that mtDNA as foreign DNA - the same way it flags a virus's DNA - and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.

The researchers hope to map out more of this complicated mtDNA-disposal and immune-activation pathway, including what biological circumstances - like mtDNA replication dysfunction and viral infection - are required to initiate the pathway and what downstream effects there may be on human health. They also see an opportunity for therapeutic innovation using this pathway, which represents a new cellular target to reduce inflammation.

Obesity in midlife is a modifiable risk factor for dementia; however, in later life, a higher body mass index (BMI) has a protective effect. This discordance in findings might be due to the reverse causation of weight loss beginning approximately 10 years before the onset of dementia. It is also possible that BMI does not adequately reflect nutritional status (degree of obesity or weight loss) in later life. This discrepancy arises because older adults usually experience changes in body composition in which fat mass increases and fat-free mass decreases with age, although the change in BMI is small.

In this context, recent studies have measured abdominal adiposity using waist circumference (WC) and waist-hip ratio, but not BMI, to assess nutritional status. Higher WC and waist-hip ratio are associated with the development of dementia and brain structural changes, such as hippocampal atrophy and white matter hyperintensity, in later life. Based on the results of these studies, the accumulation of abdominal adiposity may have an adverse effect on brain health in later life.

This study investigated the association between abdominal adiposity at baseline and change in cognitive function in community-dwelling older adults using longitudinal data collected separately for men and women over 10 years. Cognitive function was evaluated biennially using the Mini-Mental State Examination (MMSE) over 10 years. Waist circumference (WC) was measured at the naval level, and subcutaneous fat area (SFA) and visceral fat area (VFA) were assessed using baseline computed tomography scans.

This study included 873 older adults. In men, the groups with the highest levels of WC, SFA, and VFA exhibited a greater decline in MMSE score than the groups with the lowest levels, with standardized coefficient β: WC, -0.12; SFA, -0.13; VFA, -0.11. In women, the group with the highest level of WC and SFA showed a greater decline in MMSE score than the group with the lowest level, with β: WC, -0.12; SFA, -0.18), but VFA was not associated with cognitive decline.

Aging brings about a myriad of degenerative processes throughout the body. A decrease in cognitive abilities is one of the hallmark phenotypes of aging, underpinned by neuroinflammation and neurodegeneration occurring in the brain. This review focuses on the role of different immune receptors expressed in cells of the central and peripheral nervous systems.

We will discuss how immune receptors in the brain act as sentinels and effectors of the age-dependent shift in ligand composition. Within this 'old-age-ligand soup,' some immune receptors contribute directly to excessive synaptic weakening from within the neuronal compartment, while others amplify the damaging inflammatory environment in the brain. Ultimately, chronic inflammation sets up a positive feedback loop that increases the impact of immune ligand-receptor interactions in the brain, leading to permanent synaptic and neuronal loss.

Adipose-derived stem cells (ADSCs) have been widely applied in translational and regenerative medicine. However, during aging, there is a recognized functional decline in ADSCs, which compromises their therapeutic effectiveness. Currently, the mechanisms of aging-induced stem cell dysfunction remain unclear. Hence, there is a need to elucidate these mechanisms and propose strategies for reversing this functional impairment.

In this study, we found that ADSCs isolated from old donors (O-ADSCs) presented inferior phenotypes and decreased miR-145-5p levels compared to those from young donors (Y-ADSCs). To interrogate the role of miR-145-5p in ADSCs, gain- and loss-of-function approaches were performed. The results indicated that miR-145-5p overexpression in O-ADSCs promoted cellular proliferation and migration, while reducing cell senescence. Further study demonstrated that miR-145-5p could regulate ADSCs function by targeting bone morphogenetic protein binding endothelial cell precursor-derived regulator (BMPER), which is a crucial modulator in angiogenesis. Moreover, in vivo experiments showed that miR-145-5p-overexpressing O-ADSCs accelerated wound healing by promoting wound re-epithelialization and angiogenesis.

Collectively, this study indicates that miR-145-5p works as a positive regulator for optimizing O-ADSCs function, and may be a novel therapeutic target for restoring aging-associated impairments in stem cell function.