Biogerontology最新文献

Aging is a dysbiotic and pro-inflammatory process that increases susceptibility to multiple chronic comorbidities. Centenarians and supercentenarians offer a unique biological model for elucidating the molecular determinants of healthy aging and exceptional longevity, as they display distinctive epigenetic signatures and a gut microbiome configuration that diverges from both younger and typically aging individuals, although substantial interindividual variability exists. The gut microbiota constitutes a strategic hub of microorganisms and bioactive metabolites with probiotic and postbiotic potential that modulate host epigenetic circuits through precursors and substrates for epigenetic "writer" and "eraser" enzymes, thereby shaping the aging trajectory. In this review, we examine the interactions between the microbiota and its metabolites, including short-chain fatty acids, lipopolysaccharides, trimethylamine N-oxide (TMAO), p-cresol, and secondary bile acids, and their roles in epigenetic modulation associated with healthy aging. We highlight (i) the attenuation of classical pro-inflammatory pathways through downregulation of NF-κB/COX-2, modulation of the Th17/Treg balance, and also the lower systemic LPS levels of centenarians, which are associated with enhanced SIRT1 activity (↑LPS/↓SIRT1); (ii) the reprogramming of energy metabolism via activation of SIRT1/AMPK and SIRT1/p-53, modulation of mTOR, and attenuation of the IGF-1/insulin axis; (iii) the strengthening of the intestinal barrier through upregulation of tight junction proteins such as ZO-1, occludin, and claudins, resulting in reduced permeability and zonulin levels; and (iv) the optimization of antioxidant defenses. Collectively, these findings suggest translational potential for microbiota-derived metabolites in gerobiotic strategies, although clinical evidence remains limited.

Chronic stress has been linked to mitochondrial dysfunction and impaired telomere maintenance, yet the mechanistic relationships connecting these pathways in humans remain poorly resolved. Using longitudinal findings from the Guillén-Parra cohort as a motivating human example, this Perspective offers a reinterpreted framework that proposes a unifying energetic interpretation in which bioenergetic insufficiency-defined as a mismatch between stress-induced energetic demand and mitochondrial throughout-rather than accumulated molecular damage, forms the upstream constraint linking stress physiology, mitochondrial performance, and telomerase regulation. In this cohort, lower baseline mitochondrial energetic capacity predicted greater longitudinal declines in telomerase activity, while telomere length remained stable across the short observation window, supporting the view that telomerase activity represents an early, energy-sensitive marker of unresolved stress adaptation, whereas telomere shortening is a delayed structural consequence. Interpreted within the Exposure-Related Malnutrition (ERM) framework, these patterns suggest that repeated activation of stress-response pathways without adequate metabolic recovery limits mitochondrial throughput and progressively compromises genome maintenance. In contrast, repeated exposure to mild stressors followed by sufficient recovery promotes adaptive strengthening of mitochondrial function and telomeric maintenance, consistent with physiological hormesis. We outline a roadmap integrating telomerase activity with dynamic indices of mitochondrial and redox function, including NAD⁺ availability, and emerging biomarkers of systemic energetic strain, such as circulating cell-free mitochondrial DNA and GDF15. By reframing aging phenotypes as early-stage failures of energetic resolution, this model highlights modifiable windows of vulnerability and hormesis-informed strategies-including exercise-induced adaptive stress, circadian alignment, and nutritional sufficiency-as actionable pathways for preserving mitochondrial resilience and telomere maintenance.

Exposure to fine particulate matter (PM2.5) triggers pulmonary inflammation and oxidative stress, which can lead to cellular senescence and a decline in lung function. Curcumin, a yellow polyphenol derived from the rhizome of Curcuma longa, is traditionally used to treat respiratory ailments. However, its potential to counteract PM2.5-induced pulmonary senescence remains underexplored. In this study, we established a murine model of PM2.5-triggered lung senescence and used BEAS-2B cells to investigate the mechanisms of curcumin. We assessed senescence markers (p16, p21, and senescence-associated β-galactosidase [SA-β-gal]) and evaluated pulmonary function. Levels of inflammatory cytokines (e.g., interleukin-1β [IL-1β], interleukin-6 [IL-6], and tumor necrosis factor-α [TNF-α]) and oxidative stress markers (e.g., malondialdehyde [MDA], superoxide dismutase [SOD], catalase [CAT], and reactive oxygen species [ROS]) were also measured. To elucidate the underlying mechanism, we examined the expression of proteins in the mammalian target of rapamycin (mTOR)/S6K1 pathway. PM2.5 exposure induced senescence, as shown by increased levels of p16, p21, and SA-β-gal, accompanied by impaired lung function. These changes coincided with elevated pro-inflammatory mediators and increased oxidative stress. PM2.5 exposure also activated the mTOR/S6K1 pathway. Curcumin treatment attenuated the senescence markers and improved lung function. It reduced oxidative stress (e.g., lowered MDA and ROS levels) and enhanced the activity of antioxidant enzymes (SOD and CAT). Curcumin also effectively inhibited mTOR/S6K1 signaling. However, its protective effects were diminished by MHY1485, an mTOR activator, which exacerbated senescence, inflammation, and oxidative stress. These findings suggest that curcumin alleviates PM2.5-induced pulmonary senescence, likely through a hormetic effect that inhibits excessive activation of the mTOR/S6K1 axis. This study highlights the translational potential of curcumin as a phytochemical intervention against PM2.5-associated respiratory damage.

Aging adipose tissue is a consequence of organismal aging and an "amplifier" that drives systemic metabolic disorders. This review proposes the conceptual framework of the "aging metabolic amplifier", systematically explaining how aging adipose tissue reshapes the microenvironment of distant organs through its secretory profile, thereby linking obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases. The concept of the "aging metabolic amplifier" emphasizes the important role of senescent adipocytes in systemic metabolic dysfunction, and systematically elaborates on their heterogeneous characteristics, autonomous and non-autonomous changes, as well as their mechanisms in ectopic lipid deposition, cardiovascular diseases, and cognitive decline. Currently, specific intervention strategies-such as activating the thermogenic program, eliminating senescent cells, regulating autophagy, and improving the microenvironment- have been proposed, providing potential therapeutic directions for delaying aging and related metabolic diseases.

Objectives: To evaluate whether oxygen-ozone therapy (OOT) can modulate aging by inducing adaptive chaos in the HMGB1-Nrf2 redox-inflammatory pathway.

Methods: A computational systems biology model simulated feedback loops among ROS, Nrf2, HMGB1, and NF-κB under varying ozone doses and cellular contexts (protective vs. autophagy-deficient).

Results: Intermediate ozone doses in the model triggered controlled chaos. The model suggests a potential 'chaotic window' (30-40 μg/mL ozone) that may promote redox resilience in autophagy-deficient cells.

Conclusion: OOT may potentially contribute to healthy aging by modulating redox adaptability. Its theoretical effectiveness is dose-dependent, with maximal benefit in aged or dysfunctional systems requiring reactivation of flexible stress responses. However, while the model offers insights into possible dynamic behaviours of the redox-inflammatory axis under ozone exposure, it is not yet calibrated to biological data and cannot predict real-world outcomes without further experimental support.

Polyphenols are emerging as promising candidates for promoting healthy aging and neuroprotection. Here, we investigated the effects of quercetin (Q), luteolin (L), and 3-O-methylquercetin (3OMQ), individually and in combination (FORM), on lifespan, healthspan, and neurobehavioral functions in Caenorhabditis elegans. Wild-type and mutant strains (including daf-2, daf-16, and skn-1) were exposed to the compounds, followed by assessments of longevity, motility, senescence biomarkers (lipofuscin and red autofluorescence), and neuroprotection against PTZ- and methylmercury-induced damage. 3OMQ and FORM significantly extended lifespan (+ 20-24%) and improved motility and stress resilience, with effects dependent on the DAF-16/FOXO and SKN-1/Nrf2 pathways, but independent of DAF-2/IGF1R signalling. Both compounds induced DAF-16 nuclear translocation and upregulated SKN-1 expression. Furthermore, they attenuated neurodegeneration and cholinesterase hyperactivity following manganese and methylmercury exposure. These findings support the potential of 3OMQ and its polyphenol combination as anti-aging and neuroprotective agents, acting through conserved longevity and oxidative stress pathways.

Aging is marked by progressive dysfunction in cellular maintenance pathways, including mitochondrial impairment, reduced autophagic capacity, and accumulation of senescent cells, which contribute to chronic low-grade inflammation. The transmembrane protein CD47 best known for delivering a "don't eat me" signal through SIRPα is increasingly recognized as an important modulator of several aging-related processes. Its upregulation in aged or inflamed tissues can inhibit the clearance of damaged or senescent cells, reinforce inflammatory signaling through pathways such as NF-κB, and influence metabolic and autophagy-related regulation in a context-dependent manner. This review synthesizes current evidence identifying CD47 as an integrative node that intersects with multiple hallmarks of aging. We examine its roles across cardiovascular, neurodegenerative, and metabolic pathologies, and evaluate the emerging therapeutic landscape targeting the CD47-SIRPα axis. Although CD47 blockade has shown promise in enhancing immune clearance and improving tissue homeostasis, clinical translation remains challenged by on-target toxicities such as anemia and by age-dependent variability in immune responsiveness. Targeting CD47 therefore represents a mechanistically grounded but inherently complex strategy for mitigating age-related functional decline.

Iron homeostasis which is primarily regulated through intestinal iron absorption, is usually disrupted in the elderly. But changes of intestinal iron absorption with aging have not been elucidated. This study aims to investigate the role of intestinal iron absorption in driving age-related disruption of iron homeostasis. Male C57BL/6 J mice aged 2, 12, 18, and 24 months were utilized in this study to analyze age-related changes in systemic iron status, detect the alterations in intestinal iron absorption via Ussing Chamber, and clarify its regulatory mechanisms during aging via western blot and RT-qPCR. Results showed that iron deposition occurred in the liver, heart, brain, spleen, and kidney with age. Furthermore, intestinal iron absorption elevated in aged mice, particularly in the duodenum, which was accompanied by upregulated DMT1 and FPN. As FPN is the only known iron exporter in enterocytes, the upregulation of FPN was considered as the key factor of higher iron absorption during aging. Then factors influencing FPN expression were determined. It was found that serum hepcidin and hepatic Hamp mRNA levels significantly decreased. And a reduction of over 40% in p-SMAD1/5/8 which is a transcriptional regulator of hepcidin was observed. Overall, these findings suggested that the downregulation of p-SMAD is a key factor limiting the transcription of hepcidin during aging, then increased the expression of intestinal FPN, further resulting in increased iron absorption and iron homeostasis imbalance. This study demonstrated that dysregulation of the hepcidin production during aging is a key driver of iron homeostasis disruption in the elderly, representing a target for precision intervention.

Background: Epigenetic age acceleration (EAA) is a biomarker of biological aging associated with multiple diseases. Plasma metabolites are potential targets for disease prevention. Therefore, our study aims to investigate the association between plasma metabolites and EAA.

Methods: Statistics of plasma metabolites and EAA were obtained from the GWAS database. After rigorously screening the instrumental variables, we applied five Mendelian randomization methods to evaluate the relationship between each metabolite and the EAA. The robustness of the results was verified by a series of sensitivity analyses, and metabolic pathway enrichment analysis was performed for significantly associated metabolites.

Results: Our analysis identified 149 plasma metabolites associated with EAA (p < 0.05), including 46 metabolites associated with IEAA, 47 with HannumAge, 38 with GrimAge, and 41 with PhenoAge. Among these, palmitoylcarnitine levels remained correlated with EAA after multiple testing correction (P_FDR < 0.05). In the enrichment analysis, 13 metabolic pathways were associated with EAA. Among them, "cysteine and methionine metabolism" was identified as the most significantly enriched pathway (P_FDR < 0.1), and 3 metabolites in this pathway were correlated with EAA.

Conclusion: These results demonstrated that plasma metabolomics, particularly amino acid and lipid metabolism, were associated with EAA and aging. The "cysteine and methionine metabolism" pathway emerged as a potential mechanism of aging, and may underpin metabolic alterations during the aging process, and its metabolites, such as methionine, 5-methylthioadenosine, and α-ketobutyrate, may serve as intervention targets.