Falls are the second leading cause of accidental injury-related deaths among Taiwanese adults aged 65 and older. This study examined the association between Fried frailty phenotypes and fall risk in this population.

Medial vascular calcification is highly prevalent in advanced age and chronic kidney disease (CKD), where it is associated with increased risk for cardiovascular events and mortality. Vascular smooth muscle cells (VSMCs) actively regulate this process, which can be augmented by inflammation and cellular senescence. Thus, the present study investigated the impact of fisetin, a flavonol with anti-inflammatory and senolytic properties, on VSMC calcification. Fisetin treatment suppressed calcific marker expression and calcification of VSMCs as well as p38 MAPK phosphorylation induced by pro-calcific conditions. These effects were abolished by silencing of dual-specificity phosphatase 1 (DUSP1), a negative regulator of p38 MAPK activity. Moreover, knockdown of DUSP1 alone was sufficient to increase calcific marker expression in VSMCs, effects blunted by pharmacological p38 MAPK inhibition. Accordingly, DUSP1 knockdown aggravated calcification of VSMCs during pro-calcific conditions. In addition, fisetin ameliorated the effects of uremic conditions in VSMCs exposed to serum from dialysis patients. Fisetin also inhibited vascular calcification as well as calcific marker expression in mouse aortic explants exposed to high phosphate and in a cholecalciferol overload mouse model. In conclusion, fisetin acts as a potent anti-calcific agent during VSMC calcification, an effect involving DUSP1-mediated regulation of p38 MAPK-dependent pro-calcific signaling.

Multiple myeloma (MM) is a cancer that is difficult to be diagnosed and treated. This study aimed to identify programmed cell death (PCD)-related molecular subtypes of MM and to assess their impact on patients' prognosis, immune status, and drug sensitivity.

Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER () gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure. While, as we previously reported, depleted NAD causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial NAD changes in WS and the impact on WS pathologies were unknown. We show that loss of WRN increases senescence in mesenchymal stem cells (MSCs) likely related to dysregulation of metabolic and aging pathways. In line with this, NAD augmentation, via supplementation with nicotinamide riboside, reduces senescence and improves mitochondrial metabolic profiles in MSCs with knockout () and in primary fibroblasts derived from WS patients compared to controls. Moreover, deficiency results in decreased mitochondrial NAD (measured indirectly via mitochondrially-expressed PARP activity), and altered expression of key salvage pathway enzymes, including NMNAT1 and NAMPT; ChIP-seq data analysis unveils a potential co-regulatory axis between WRN and the NMNATs, likely important for chromatin stability and DNA metabolism. However, restoration of mitochondrial or cellular NAD is not sufficient to reinstall cellular proliferation in immortalized cells with siRNA-mediated knockdown of , highlighting an indispensable role of WRN in proliferation even in an NAD affluent environment. Further cell and animal studies are needed to deepen our understanding of the underlying mechanisms, facilitating related drug development.

The dynamic nature of epigenetic modifications has been leveraged to construct epigenetic clocks that accurately predict an individual's age based on DNA methylation levels. Here we explore whether the accumulation of epimutations, which can be quantified by Shannon's entropy, changes reproducibly with age. Using targeted bisulfite sequencing, we analyzed the associations between age, entropy, and methylation levels in human buccal swab samples. We find that epigenetic clocks based on the entropy of methylation states predict chronological age with similar accuracy as common approaches that are based on methylation levels of individual cytosines. Our approach suggests that across many genomic loci, methylation entropy changes reproducibly with age.

Alzheimer Disease (AD) affects more than 50 million people worldwide, with 10 million new diagnosis each year. The link between Sildenafil, a Phosphodiesterase-5 (PDE5) inhibitor, and risk of AD has been debated. We conducted the first meta-analysis on the association between Sildenafil use and risk of AD.

Epigenetic age, estimated by DNA methylation across the genome, reflects biological age. Accelerated age (i.e., an older methylation age than expected given chronological age) is an accepted aging biomarker in humans, showing robust associations with deleterious health outcomes, longevity, and mortality. However, data regarding age acceleration in nonhuman primates (NHPs), and relationships between NHP epigenetic age and behavioral indicators of aging, such as walking speed and fine motor performance, are sparse. We measured DNA methylation of 140 captive olive baboons () (84% female, 3-20 years-old), estimated their epigenetic ages, and classified them as showing age acceleration or deceleration. We found that epigenetic age was strongly correlated with chronological age, and that approximately 27% of the sample showed age acceleration and 28% showed age deceleration. We subsequently examined relationships between epigenetic and accelerated age and walking speed (N=129) and fine motor performance (N=39). Older animals showed slower speeds and poorer motor performance. However, the difference between the epigenetic age and chronological age, referred to as delta age, was not a consistent predictor of walking speed or fine motor performance. These data highlight the need for further examination of age acceleration across NHP species, and the ways that age acceleration may (not) be related to indicators of aging in NHP models.

Exercise-induced mechanical load stimulates bone cells, including osteocytes, to promote bone formation. The bone response to loading is less effective with aging, but the cellular and molecular mechanisms responsible for the impaired mechanoresponsiveness remain unclear. Excessive mitochondrial reactive oxygen species (mtROS) and deficient autophagy are common aging mechanisms implicated in decreased bone formation in old mice. Here, we confirmed that the osteogenic effects of tibia compressive loading are lower in old versus young female mice. We also examined whether an increase in mtROS or decreased autophagy in osteoblast-lineage cells of adult female mice could mimic the deleterious effects of aging. To this end, we loaded mice lacking the antioxidant enzyme superoxide dismutase 2 () or autophagy-related 7 () in cells targeted by Osterix1 (Osx1)-Cre. Osteocytes in exhibited altered morphology and decreased osteocyte dendrite projections. Two weeks of loading increased cortical bone mass and bone formation rate at both periosteal and endosteal surfaces of Osx1-Cre control mice. Nonetheless, in both and mice the response to loading was identical to that observed in control mice, indicating that compromised -dependent autophagy or excessive mtROS are not sufficient to impair the bone response to tibial compressive loading. Thus, alternative mechanisms of aging might be responsible for the decreased response of the aged skeleton to mechanical stimuli. These findings also suggest that an intact osteocyte dendrite network is not required for the osteogenic response in this model of bone loading.

As humans age, some experience cognitive impairment while others do not. When impairment does occur, it is not expressed uniformly across cognitive domains and varies in severity across individuals. Translationally relevant model systems are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brain's susceptibility to the effects of aging. As such, non-human primates (NHPs) are particularly important due to shared behavioral, neuroanatomical, and age-related neuropathological features with humans. For many decades, macaque monkeys have served as the primary NHP model for studying the neurobiology of cognitive aging. More recently, the common marmoset has emerged as an advantageous model for this work due to its short lifespan that facilitates longitudinal studies. Despite their growing popularity as a model, whether marmosets exhibit patterns of age-related cognitive impairment comparable to those observed in macaques and humans remains unexplored. To address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we directly compared working memory ability as a function of age in macaques and marmosets on the identical task. We also implemented varying delays to further tax working memory capacity. Our findings demonstrate that marmosets and macaques exhibit remarkably similar age-related working memory deficits, with macaques performing better than marmosets on longer delays. These results highlight the similarities and differences between the two most commonly used NHP models and support the value of the marmoset as a model for cognitive aging research within the neuroscience community.

There is no doubt that maternal aging, also known as reproductive aging, can contribute to the increased rates of aneuploidy observed in blastocysts generated from women of advanced age who undergo fertilization (IVF). Additionally, the hatching process of the blastocyst, which is crucial for successful implantation, may be impaired in aneuploid embryos. Aneuploid embryos often exhibit abnormal cell division and chromosomal distribution, which can lead to disruptions in the hatching process. Due to ethical restrictions, preimplantation genetic testing for aneuploidy (PGT-A) is unavailable in all countries. Therefore, our retrospective study of 502 couples who underwent intracytoplasmic sperm injection (ICSI) aimed to elucidate if embryonic features, such as the ability to hatch and embryonic diameter, could be a reliable estimator for the success rate after embryo transfer, especially for women aged 26-45 years, and for IVF clinics which do not have access to PGT-A. The small hatching blastocysts (Bl. 5) group had a significant ( < 0.001) higher percentage of euploid embryos (≤35 Y- 73%, >35Y- 51%) compared to large (Bl. 4) counterparts (≤35 Y-58%, >35 Y- 38%). In patients aged 34-38 years, we detected 10% more euploid blastocysts in the hatching group than the expanding ones, which was a significant difference ( < 0.05). In conclusion, when selecting non-PGT-A tested embryos for embryo transfer (ET) or frozen embryo transfer (FET), a small hatching blastocyst seems to be a better choice than a large expanded one, especially for advanced-age patients for whom the risk of aneuploidy is higher.

Numerous studies have investigated the effects of various interventions on the lifespans of mice and rats. The design of future rodent lifespan extension experiments might consider experimental parameters used in earlier investigations, but finding and reviewing all previous experiments requires a substantial resource investment. Additionally, when studied collectively, the results of previous investigations might suggest fundamental mechanisms causing age-related degeneration. Here, we report our efforts to find and aggregate data from all research reports of lifespan extension in mice or rats, which we call the "Rodent Aging Interventions Database" (RAID). We identified studies for inclusion using complex PubMed queries and by nomination from our colleagues in the field. The relevant data from each study was manually extracted and recorded in a table. A publicly available, web-based software tool was then created to enable users to visualize and filter this data in a convenient manner. Our current dataset, covering publications up to October 2022, includes 121 unique studies reporting on 212 distinct intervention protocols that extended lifespan in mice or rats. We intend to periodically update our dataset as new rodent lifespan studies are reported. RAID is publicly available at https://levf.org/raid.

Cellular senescence is a hallmark of aging and the age-related condition, Alzheimer's disease (AD). How senescence contributes to cholinergic and neuropathologic changes in AD remains uncertain. Furthermore, little is known about the relationship between senescence and cholinesterases (ChEs). Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are important in neurotransmission, cell cycle regulation, and AD amyloid-β (Aβ) pathology. Senolytic agents have shown therapeutic promise in AD models. Therefore, we evaluated and activity of senolytics, dasatinib (1), nintedanib (2), fisetin (3), quercetin (4), GW2580 (5), and nootropic, meclofenoxate hydrochloride (6), toward AChE and BChE. As ChEs associated with AD pathology have altered biochemical properties, we also evaluated agents 1-6 in AD brain tissues. Enzyme kinetics showed agents 1, 3, 4, and 6 inhibited both ChEs, while 2 and 5 inhibited only AChE. Histochemistry showed inhibition of Aβ plaque-associated ChEs (1 and 2: both ChEs; 5: BChE; 6: AChE), but not normal neural-associated ChEs. Modeling studies showed 1-6 interacted with the same five binding locations of both ChEs, some of which may be allosteric sites. These agents may exert their beneficial effects, in part, by inhibiting ChEs associated with AD pathology and provide new avenues for development of next-generation inhibitors targeting pathology-associated ChEs.

Breast cancer (BC) survivors may experience accelerated aging due to detrimental effects of BC and/or its treatments. Our study aims to evaluate Phenotypic Age Acceleration (PAA), a biological age measure, among BC patients and assess its associations with cancer characteristics and treatments. In this study including 1264 BC patients (age 54.7±11.7) and 429 cancer-free controls (age 49.9±12.4), we evaluated the differences in PAA (ΔPAA) by BC characteristics and treatments at multiple time points using linear mixed models. Overall, BC survivors had a higher PAA than controls at diagnosis (ΔPAA=3.73, <0.001), 1-year (ΔPAA=1.68, =0.001), and 10-year (ΔPAA=1.16, =0.03) post-diagnosis. At 10-year post-diagnosis, stage III/IV (vs 0), intermediate- and high- (vs low-) grade BC were associated with a higher PAA of 4.48 (<0.001), 1.26 (=0.03), and 1.95 (=0.001), respectively; triple-negative (vs hormone receptor+/HER2-) BC was associated with a lower PAA (ΔPAA=-1.96, =0.004). Compared with patients receiving surgery with or without radiotherapy, higher PAA was observed at 1-year post-diagnosis among those receiving additional chemotherapy (ΔPAA=4.26, <0.001) and at 10-year post-diagnosis for endocrine therapy (ΔPAA=2.89, =0.001). In conclusion, BC patients had accelerated aging up to 10 years post-diagnosis, especially among those with stage III/IV and high/intermediate-grade BC, and receiving systemic treatment.

Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely linked to vitamin D deficiency. This study examines the role of Sirtuin 1 (Sirt1) and its regulation by vitamin D in preventing sarcopenia. Utilizing wild-type, 1α-hydroxylase knockout (1α(OH)ase), and Sirt1 transgenic (Sirt1) 1α(OH)ase mice, we investigated muscle Sirt1 levels, muscle mass, fiber type, and senescence markers. Our results demonstrated that 1,25-Dihydroxyvitamin D (1,25(OH)2D3) upregulated Sirt1 and myogenic factor MyoD1 expression in C2C12 myoblasts via VDR-mediated transcription. Sirt1 overexpression in mesenchymal stem cells (MSCs) significantly mitigated muscle mass reduction, improved fiber cross-sectional area, and increased type II fiber numbers in 1α(OH)ase mice. Mechanistically, 1,25(OH)2D3 promoted muscle cell health by enhancing Sirt1 expression, which in turn reduced muscle cell senescence and the senescence-associated secretory phenotype (SASP) through decreased levels of acetylated nuclear p53 and p65, maintaining their cytoplasmic localization. Additionally, Sirt1 overexpression accelerated muscle regeneration post-injury by increasing embryonic myosin heavy chain expression and cell proliferation. These findings underscore the therapeutic potential of targeting vitamin D and Sirt1 pathways to prevent sarcopenia, suggesting that supplementation with active vitamin D and consequent Sirt1 activation could be effective strategies for managing age-related muscle wasting.

Aging interventions have progressed in recent years due to the growing curiosity about how lifestyle impacts longevity. This study assessed the effects of SRW Laboratories' Cel System nutraceutical range on epigenetic methylation patterns, inflammation, physical performance, body composition, and epigenetic biomarkers of aging. A 1-year study was conducted with 51 individuals, collecting data at baseline, 3 months, 6 months, and 12 months. Participants were encouraged to walk 10 minutes and practice 5 minutes of mindfulness daily. Significant improvements in muscle strength, body function, and body composition metrics were observed. Epigenetic clock analysis showed a decrease in biological age with significant reductions in stem cell division rates. Immune cell subset analysis indicated significant changes, with increases in eosinophils and CD8T cells and decreases in B memory, CD4T memory, and T-regulatory cells. Predicted epigenetic biomarker proxies (EBPs) showed significant changes in retinol/TTHY, a regulator of cell growth, proliferation, and differentiation, and deoxycholic acid glucuronide levels, a metabolite of deoxycholic acid generated in the liver. Gene ontology analysis revealed significant CpG methylation changes in genes involved in critical biological processes related to aging, such as oxidative stress-induced premature senescence, pyrimidine deoxyribonucleotide metabolic process, TRAIL binding, hyaluronan biosynthetic process, neurotransmitter loading into synaptic vesicles, pore complex assembly, collagen biosynthetic process, protein phosphatase 2A binding activity, and activation of transcription factor binding. Our findings suggest that the Cel System supplement range may effectively reduce biological age and improve health metrics, warranting further investigation into its mechanistic pathways and long-term efficacy.

Inflammation plays a pivotal role in the age-related decline of skeletal muscle mass, leading to sarcopenia in the elderly. The prevalence of sarcopenia notably increases among males aged ≥ 70. However, it remains unclear whether inflammatory indexes are associated with the reduction in skeletal muscle mass in the elderly population. Thirty-one males aged ≥ 70, without severe diseases or dementia, were enrolled in the study. They underwent muscle mass measurements, physical measurements, and hematological tests at the onset of the study and after a one-year follow-up. Twenty-eight participants were successfully followed for one year. Appendicular skeletal muscle mass index (ASMI) decreased by 3.30 ± 2.41% in 14 participants and increased by 2.66 ± 1.61% in the other 14 participants compared to baseline levels. The baseline neutrophil-to-lymphocyte ratio (NLR) was 2.14 ± 0.56 in the ASMI-decreased group and 1.66 ± 0.62 in the ASMI-increased group. A statistically significant negative correlation was found between baseline NLR and the change in ASMI in linear regression analyses. The area under the curve (AUC) of the baseline NLR for predicting ASMI decline was 0.724, with an optimal sensitivity of 64.3% and specificity of 78.6% at a cut-off value of 1.94. NLR emerged as a potential prognostic marker for ASMI reduction in elderly males. However, further studies are necessary to assess its clinical utility.

Natural killer (NK) cells are known for their cytotoxic and cytokine secretion capabilities. The balance of activating and inhibitory receptors on their surface regulates NK cell function and survival. However, it is not fully understood how aging may modulate the levels of NK cell surface receptors ultimately affecting their interaction with other immune cells, especially with those known to activate and expand NK cells. Here, we report decreased levels of NK cells' surface receptors, cytotoxic function, and cytokine secretion in aged donors (75-85 years) as compared to younger donors (21-25 years). We used our previously established methodology to expand and supercharge NK cells from young and older individuals using osteoclasts (OCs) and probiotic bacteria. Significantly lower levels of NK cell expansion and functional activation were seen in NK cells from 75-85-year-old donors when compared to younger donors' NK cells. Surface receptors of OCs were also found to be decreased in 75-85-year-old donors compared to younger donors. In addition, OCs from 75-85-year-old donors induced lower levels of cell expansion and functional activation of NK cells when compared to OCs from younger donors. These findings illustrate defects in both peripheral blood-derived primary NK cells and OCs in older individuals; however, suppression appears to be more in NK cells when compared to OCs.

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified (the drosophila orthologue of mammalian ) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of resulted in reduced gut permeability, DNA damage, and expression of the senescence marker β-galactosidase (SA-β-gal) in the fly gut following irradiation. Additionally, inhibition of in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where knockdown or pharmacological inhibition decreased expression of specific SASP factors and SA-β-gal. Furthermore, proteomics analysis of the secretory factor of senescent cells revealed a significant decrease in SASP factors associated with the cleavage site. These data suggest that inhibition could represent a novel senomorphic strategy.