Longevity Papers

Influenza A virus (IAV) infection causes significantly greater morbidity and mortality in the elderly population, but the molecular mechanisms in the aging process responsible for severe infection remain unclear. In this study, we found that increased severity in IAV infection and reduced innate immune response correlated with extensive mitophagy in senescent human cells and in the lung of aged mice. Apolipoprotein D (ApoD) was identified as strongly elevated in the lungs and sera of aged human (>65 y old) and mouse (>21 mo old). ApoD was able to localize to mitochondria and interact, through its WXXI motif in the LC3B-Interacting Region domain, with LC3B to trigger mitophagy during IAV infection, in a PINK1 pathway independent manner, which attenuated type I interferon response and promoted virus replication. ApoD deficiency, on the other hand, protected older mice from severe influenza and improved survival. Likewise, depletion of senescent cells by ABT-263, a senolytic compound, in aged mice lowered ApoD level and restored innate immune antiviral response, limiting virus propagation and associated pulmonary damage. Thus, age-induced ApoD drives IAV-mediated mitophagy, and promotes virus replication and infection severity, and is therefore a promising target for inhibition to improve disease outcome in older patients.

The mechanisms linking hearing ability, inflammation, glymphatic system function, and cognitive impairment in older adults are largely unknown. To investigate this issues, magnetic resonance imaging (MRI) was used to test for dysfunctions in the glymphatic system of older adults with hearing loss and to determine the relationship of glymphatic dysfunction, inflammation and cognitive deficits. This cross-sectional observational study included participants with ARHL and healthy controls (HCs) between January 2021 and December 2023. Participants underwent MRI scans of the glymphatic indices and clinical assessment of auditory, neuropsychological, and inflammatory measures. Multimodal MRI indices were used as proxies of glymphatic function and compared with measures of inflammation and cognition dysfunction in the older adults with hearing loss and control groups. Mann-Whitney U test, Spearman rank correlation and Mediation analysis were conducted. A total of 130 hearing loss patients (mean age years, 64.10 ± 3.43 [SD], 67 males) and 121 healthy controls (mean age years, 63.55 ± 3.49 [SD], 68 males) were included. The hearing loss group differed significantly from normal hearing control on MRI glymphatic measures of choroid plexus volume (CPV) (1.48 vs 1.37, p = 0.0004), enlarged perivascular spaces (EPVS) (1.74 vs 1.55, p < 0.0001) and diffusion tensor image analysis along the perivascular space (DTI-ALPS) (1.47 vs 1.63, p < 0.0001). Hearing loss severity was associated with higher values of CPV and EPVS and lower values of ALPS and strongly correlated with higher levels of inflammation (all FDR q < 0.05). Mediation analysis showed that ALPS and CPV mediate the relationship between hearing loss and scores on the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST), respectively. Our findings support a potential associative pathway that inflammation and glymphatic dysfunction act as plausible intermediate factors facilitating the pathological relationship linking the increase in hearing loss in older adults to decline in cognition.

Due to the paucity of longitudinal DNA methylation data (DNAm), especially among Hispanic/Latino adults, the association between changes in epigenetic clocks over time and cognitive aging phenotypes has not been investigated. This longitudinal study included 2671 Hispanic/Latino adults (57 years; 66% women) with blood DNAm data and neurocognitive function assessed at two visits ~7 years apart. We evaluated the associations of 5 epigenetic clocks and their between-visit change with multiple measures of cognitive aging that included a global and domain-specific cognitive function score at each visit, between-visit change in global and domain-specific cognitive function score, and MCI diagnosis at visit 2 (V2). There were significant associations between greater acceleration of all clocks and lower cognitive function at each visit and MCI at V2. The strongest associations were observed for GrimAge and DunedinPACE. There were significant associations of between-visit increase in PhenoAge and GrimAge acceleration with decline in cognitive function and greater risk of MCI diagnosis at V2. Epigenetic aging is associated with lower global and domain-specific cognitive function, greater cognitive decline, and greater risk of MCI in Hispanic/Latino adults. Longitudinal assessment of change in age acceleration for second-generation clocks, GrimAge and PhenoAge may provide additional value in predicting cognitive aging beyond a single time point assessment.

In the past century, the human Lifespan has doubled. However, this is not equivalent to Healthspan which refers to the number of years spent healthy and free from disease. Women have an additional level of complexity on the path to optimal healthspan where health resilience dramatically decreases following menopause and this is due to their ovaries aging by midlife. It still remains elusive on why and how the ovaries in women, albeit their distinct and vital reproductive functions, start to age before any other organs. Following menopause, women are at increased risks of age-associated chronic diseases such as cardiometabolic disease, osteoporosis, sarcopenia, frailty, and neurocognitive decline. By preserving reproductive longevity through targeting the ovary as the organ to rejuvenate in women, optimal healthspan could be obtained in women. Interestingly, population studies have shown that women who conceive naturally and give birth at advanced reproductive ages are demonstrated to have superior postmenopausal longevity. Correspondingly, men Lived longer with a sister reproducing after 45 years of age in natural fertility conditions, suggesting that late female fertility and slow somatic aging may be promoted by the same genetic variants. Causal inference analysis showed a link between increased reproductive lifespan (prolonged ovarian lifespan or later age at natural menopause) and a reduction of diseases such as diabetes and osteoporosis. Essentially, fewer ovarian follicles and shorter ovarian lifespan were associated with poorer health later in life. Therefore, innovative ways to understand and target the ovaries in women for gero-protection have the potential to avert aging diseases triggered by the female menopause. Our narrative review aims to integrate existing information from systemic and reproductive aging from preclinical and human studies to devise novel methodologies to avert ovarian aging which could potentially improve the health trajectory in aging women. Similar strategies can be applied to men to achieve healthy longevity in the population. While there are certain things one has little control over, such as genetics and the inevitable reduction of reproductive hormone levels over time, there are modifiable risk factors which can be targeted to preserve reproductive longevity by uniquely targeting the ovary especially in modifying and improving the ovarian microenvironment to ensure survival of the ovarian follicles which determine true reproductive lifespan and healthspan. This can be achieved by modifying diet, sleep patterns, and exercise and limiting toxin exposure to ensure optimal ovarian health, through healthy and functional ovarian follicles, which could bring us a step closer to enhancing women's healthspan and human longevity.

The ketogenic diet (KD), a high-fat, low-carbohydrate regimen, has been shown to exert neuroprotective effects in various neurological models. This study explored how KD-alone or combined with antibiotic-induced gut microbiota depletion-affects cognition and neuroinflammation in aging. Thirty-two male rats (22 months old) were assigned to four groups (n = 8): control diet (CD), ketogenic diet (KD), antibiotics with control diet (AB), and antibiotics with KD (KDAB). Diets were maintained for 10 weeks; during the final week, AB and KDAB groups received a broad-spectrum antibiotic cocktail (ampicillin 1 g/L, vancomycin 0.5 g/L, neomycin 1 g/L, and metronidazole 1 g/L) in drinking water. Cognitive abilities were evaluated using the Morris Water Maze and Novel Object Recognition Test. BDNF and inflammatory cytokines (TNF-α, IL-1β, IL-10) were measured in the hippocampus and prefrontal cortex. KD and KDAB groups exhibited increased β-hydroxybutyrate and reduced glucose levels, enhanced cognitive performance, elevated BDNF and IL-10, and decreased TNF-α and IL-1β compared to non-KD groups. Although antibiotic treatment alone caused only a transient impairment in spatial memory and was associated with reduced TNF-α levels, the ketogenic diet-irrespective of microbiota status-consistently improved cognitive performance and elevated neuroprotective markers. These findings suggest that KD appears to promote brain resilience during aging, even in the presence of microbiota disruption.

The global surge in the population of people 60 years and older, including that in China, challenges healthcare systems with rising age-related diseases. To address this demographic change, the Aging Biomarker Consortium (ABC) has launched the X-Age Project to develop a comprehensive aging evaluation system tailored to the Chinese population. Our goal is to identify robust biomarkers and construct composite aging clocks that capture biological age, defined as an individual's physiological and molecular state, across diverse Chinese cohorts. This Perspective outlines the core objectives, methodological framework and key deliverables of the X-Age Project, including cohort recruitment, standardized sample collection, multimodal data acquisition and clock model development. By integrating interdisciplinary expertise, we aim to provide a practical and scalable platform for understanding aging complexity and heterogeneity, early detection of accelerated aging and evaluation of aging interventions.

While BAG3 has been identified as a causative gene for dilated cardiomyopathy, the major pathological events in BAG3-related cardiomyopathy that could be targeted for therapeutic benefit remain to be discovered. Here, we aim to uncover novel pathological events through genetic studies in a zebrafish bag3 cardiomyopathy model. Given the known cardioprotective effects of mtor inhibition and the fact that transcription factor EB (tfeb) encodes a direct downstream phosphorylation target of mTOR signaling, we generated a cardiomyocyte-specific transgenic line overexpressing tfeb (Tg[cmlc2:tfeb]). This overexpression was sufficient to restore defective proteostasis and rescue cardiac dysfunction in the bag3 cardiomyopathy model. Importantly, we detected accelerated cardiac senescence in the bag3 cardiomyopathy model, which can be mitigated by Tg(cmlc2:tfeb). We compared cardiac transcriptomes between the Tg(cmlc2:tfeb) transgenic fish and the mtor

The disparity between the global increase in life expectancy and the steady decline in health outcomes with age has been a major driver for developing new ways to research aging. Although this current tools for studying aging outside of the human body-such as animal models and cells in a dish-have improved this fundamental understanding of the markers and key mechanisms underlying this process, several limitations remain. Animal models are poor biological representations of humans and have a weak track record of translating pre-clinical results into successful clinical applications. Similarly, current 2D cellular models do not recapitulate the dynamic 3D environment of human tissue. This gap between the need for accurate biological mimicry and the limitations of current aging models presents an exciting opportunity for the field of biofabrication. Over the past decade, the combination of biofabrication and advanced biomaterials has shown potential to engineer high-resolution features that change over time or respond to specific stimuli. In this perspective, the current state of in vitro aging models is reflected, identify the key features that new models must emulate, discuss the technologies available to meet these complex specifications, and consider some of the potential challenges facing the field.

Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. Macrophage phenotype is metabolically controlled through TCA intermediate accumulation and activation of HIF1A. We hypothesized that transient hypoxia following disuse in old mice would enhance macrophage metabolic inflammatory function thereby improving muscle cellular remodeling and recovery. Old (20 months) and young adult mice (4 months) were exposed to acute (24h) normobaric hypoxia immediately following 14-days of hindlimb unloading and assessed during early re-ambulation (4- and 7-days) compared to age-matched controls. Treated aged mice had improved pro-inflammatory macrophage profiles, muscle cellular remodeling, and functional muscle recovery to the levels of young control mice. Likewise, young adult mice had enhanced muscle remodeling and functional recovery when treated with acute hypoxia. Treatment in aged mice restored the muscle molecular fingerprint and biochemical spectral patterns (Raman Spectroscopy) observed in young mice and strongly correlated to improved collagen remodeling. Finally, intramuscular delivery of hypoxia-treated macrophages recapitulated the muscle remodeling and recovery effects of whole-body hypoxic exposure in old mice. These results emphasize the role of pro-inflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.

Thyroid hormones (TH), primarily triiodothyronine (T3) and thyroxine (T4), are critical regulators of metabolic rate, mitochondrial function, and cellular repair mechanisms. Emerging evidence suggests that thyroid status may significantly influence aging trajectories and longevity through modulation of key cellular pathways. Objective: This review explores the role of thyroid hormones in aging biology, with a focus on their interaction with longevity-associated signaling pathways and the hallmarks of aging. Both physiological and subclinical thyroid states in the context of healthspan, cognitive preservation, metabolic resilience, and mitochondrial integrity are explored. A narrative synthesis of human and animal studies was conducted, including mechanistic, epidemiologic, and clinical data, to evaluate how thyroid hormone levels affect aging pathways such as mTOR, AMPK, IGF-1, sirtuins, FOXO transcription factors, and mitochondrial biogenesis. Thyroid hormones modulate several hallmarks of aging, including mitochondrial dysfunction, genomic instability, epigenetic drift, and deregulated nutrient sensing. T3 enhances mitochondrial respiration and autophagy while interacting with mTOR and AMPK to regulate energy balance. Altered thyroid function-particularly subclinical hypothyroidism, has been paradoxically associated with increased longevity in some centenarian cohorts, possibly due to reduced oxidative metabolism. However, overt thyroid dysfunction is linked to increased metabolic risk in aging populations. Thyroid hormones serve as metabolic gatekeepers that influence both cellular aging and organismal longevity. A deeper understanding of their role in aging pathways may inform novel strategies for promoting healthy aging, including thyroid hormone modulation, and personalized endocrine optimization.

The widely used antidiabetic drug metformin extends lifespan across diverse model organisms, from yeast to primates. However, the cellular mechanisms underlying its anti-aging effects remain only partially understood. Here, we combined large-scale genetic screening and high-resolution lifespan phenotyping with transcriptomic and proteomic analyses to provide a systems view of metformin\'s impact on the chronological lifespan of Saccharomyces cerevisiae. Unexpectedly, we uncovered pronounced gene-drug interactions between metformin and chromatin-modifying factors. Specifically, deletions of Set3C histone deacetylation complex subunits phenocopied the longevity effect of metformin, with no additive benefit when combined, suggesting convergence on shared pathways. Transcriptome profiling further revealed that metformin reprogrammed stationary-phase gene expression, with Ty1-copia retrotransposons emerging as a consistently induced signature, thereby suggesting a possible mechanism for the observed interactions with Set3C regulation. Paradoxically, TYA Gag-like protein levels and retrotransposition frequency were modestly reduced, indicating an uncoupling between transcriptional activation and retromobility. Proteome analysis revealed increased abundance of mitochondrial and stress-response proteins as primary outcomes of metformin exposure, both known modulators of Ty1 dynamics in yeast. Together, our findings position chromatin regulation and retrotransposon expression as integral components of metformin\'s pro-longevity mechanisms, expanding its influence beyond signaling, metabolism, and stress response.

Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middle-aged, and aged animals, we quantified the loss of communication efficiency over time. We considered communication channels between transcription factors (TF; 'input message') and corresponding target genes (TG; 'output message'). Mutual information (MI), defined as the information effectively transmitted between TFs and TGs, declined with age. This decline was attributed to escalating biological noise and loss of precision with which TFs regulate TGs (ie, channel capacity). When we ranked TF:TG pairs by MI, pairs associated with fatty acid oxidation displayed the greatest loss of communication with aging, while the system preserved communication between pairs related to RNA synthesis. These data suggest ineffective communication with aging against a backdrop of resource reallocation to support essential cellular functions.

Impaired proteostasis is a hallmark of aging and is associated with several neurodegenerative diseases, including Huntington\'s Disease (HD) where the polyglutamine (polyQ) expanded Huntingtin aggregates to form insoluble inclusions bodies (IBs) associated with neurotoxicity. Chronological lifespan (CLS) in yeast resembles many aspects of aging of non-dividing cells such as neurons. During chronological aging, acidification of the culture media due accumulation of acetic acid is one of the major cell-extrinsic factors contributing to age-related cell death. Thus, buffering media pH to prevent acidification significantly extends longevity. Here, we found that cells expressing pathogenic polyQ expansion proteins display increased sensitivity to acetic acid and shortened CLS. Buffering media pH promotes both polyQ aggregation into IBs and promotes longevity. We also found that growth at alkaline pH induces the activation of heat shock response (HSR) in young cells. Such hormetic HSR activation subsequently allowed aged cells to mount a proper HSR in response to stresses such as heat shock or polyQ misfolding, leading to lifespan extension. Our study thus provides new insight into how pH can promote proteotoxic stress resistance and longevity by modulating the HSR.

Lipid metabolism plays an important role in aging and longevity, and lipophagy-a specialized form of autophagy that targets lipid vesicles-regulates lipid homeostasis and alleviates metabolic diseases such as metabolic dysfunctionassociated steatotic liver disease (MASLD). Ilimaquinone (IQ), a sesquiterpene extracted from the sea, is well-known for its various biological effects; however, its effects on lipid metabolism and longevity have not yet been elucidated. In this study, IQ acted in a dose-dependent manner, extending the lifespan of Caenorhabditis elegans (C. elegans) by up to 50%, causing transcriptional changes in 1,878 genes related to fatty acid degradation and longevity pathways. Additionally, IQ reduced lipid accumulation in C. elegans and mouse AML12 cells, as confirmed by Oil Red O staining. RNA sequencing and quantitative reverse transcription polymerase chain reaction validation showed that the expression of key lipid metabolism genes, such as lipl-4 in worms and Lipa in mammalian cells, increased with IQ treatment. Lipophagy has been identified as the key mechanism underlying the lipid-lowering effects of IQ. The inhibition of autophagy by Bafilomycin A1 reversed the reduction in lipid accumulation in both C. elegans and AML12 cells, indicating the involvement of autophagic flux. Western blot analysis demonstrated that IQ activates AMPK, a key regulator of autophagy and lipid metabolism, and inhibits mTOR. IQ increased the turnover of LC3-II and decreased p62 levels, confirming autophagosome formations and increased lysosomal degradation. These findings suggest that IQ promotes autophagy, alleviates lipid accumulation, and has a therapeutic potential for metabolic diseases. In addition, AMPK activation and mTOR inhibition pathways may have contributed to the extension of C. elegans lifespan. Future studies should investigate the potential of IQ in lipid metabolism regulation and lifespan extension.

Ageing is one of the most significant risk factors for heart disease; however, it is still not clear how the human heart changes with age. Taking advantage of a unique set of pre-mortem, cryopreserved, non-diseased human hearts, we performed omics analyses (transcriptomics, proteomics, metabolomics, and lipidomics), coupled with biologically informed computational modelling in younger (≤ 25 years old) and older hearts (≥ 50 years old) to describe the molecular landscape of human cardiac ageing. In older hearts, we observed a downregulation of proteins involved in calcium signalling and the contractile apparatus. Furthermore, we found a potential dysregulation of central carbon generation of fuel, glycolysis, and fatty acids oxidation, along with an increase in long-chain fatty acids. This study presents and analyses the first molecular data set of normal human cardiac ageing, which has relevant implications for understanding the human cardiac ageing process and the development of age-related heart disease.