Biogerontology最新文献

Aging is a complex process that includes chronological aging and cellular aging. Although chronological aging is irreversible, cellular aging, which is reversible, is closely associated with chronological aging. Understanding the complexity of the impact and mechanisms of aging on the male reproductive function is crucial in maintaining male fertility. This study reviews the effects and mechanisms associated with aging in males on male reproductive health. It also provides potential therapeutic strategies for alleviating the reproductive consequences of aging in males. Evidence from the literature revealed that aging suppresses testicular steroidogenesis and circulating testosterone, lowers spermatogenesis and sperm quality, and induces erectile dysfunction. These adverse events are mediated by mitochondrial dysfunction and reduced ATP production, oxidative stress, inflammation, apoptosis, and DNA damage. More so, telomere shortening, cellular senescence, and epigenetic modification play crucial roles. Modulation of these processes with antioxidants such as vitamin C, vitamin E, CoQ10, and zinc attenuates cellular aging and promotes male reproductive health.

Aging reduces testicular function by lowering sperm quality and testosterone, worsened by diseases. Morphine addiction harms male reproduction by disrupting hormonal balance and increasing testicular oxidative stress and inflammation. Regular physical exercise can help counteract these effects by boosting antioxidants and supporting sperm production. This study explores how exercise mitigates inflammaging and testosterone decline by modulating the NF-κB signaling pathway in aged male rats with morphine addiction. A total of 56 male Wistar rats were divided into eight groups, with four groups for each age category (young and old). The experimental groups were as follows: 1) Control, 2) Trained, 3) Addicted, and 4) Trained + Addicted. Rats in the addicted groups received morphine treatment for 28 days, while the trained groups underwent treadmill exercise sessions for 4 weeks. The gene expression levels of NF-κB and Nrf2 in testis tissue were quantified using RT-PCR. Additionally, the concentrations of the cytokines TNF-α and IL-10 were measured in testis tissue by ELISA. Furthermore, the levels of MDA, TAC, and testosterone were assessed using specific assay kits. Our results demonstrated that morphine exposure in both young and old rats significantly decreased IL-10, TAC, and testosterone levels, while it increased TNF-α, MDA, and NF-κB gene expression. Exercise in both young and old groups resulted in a reduction of NF-κB gene expression, as well as decreased levels of TNF-α and MDA. Additionally, exercise increased testosterone, interleukin-10, and total antioxidant capacity in both serum and testicular tissue. Our results demonstrated that exercise mitigates testicular impairments following morphine exposure in young and old rats via reducing inflammation and oxidative stress while increasing testosterone levels and modulating NF-κB expression.

To verify whether DNA repair is regulated by FOXO3a, a tet-on flag-h-FOXO3a transgenic mice were used. RT-q-PCR and western blot analysis showed that the mRNA and protein levels of flag-h-FOXO3a, XRCC4, XPC, APE1 and MSH2 increased dose dependently by doxycycline. DNA repair activities like non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) also increased in a doxycycline dose dependent manner. MEF (mouse embryonic fibroblast) cells of the transgenic mouse were transfected with human XRCC4/XPC/APE1/MSH2 promoter-pGL3 basic vectors. Promoter assay and ChIP (chromatin immunoprecipitation) assay showed increased promoter activity and interactions of FOXO3a to FOXO consensus sites. The results indicate that XRCC4, XPC, APE1, and MSH2 are transcriptional target genes of FOXO3a and activities of NHEJ, NER, BER and MMR are regulated probably via transcriptional activation of XRCC4, XPC, APE1 and MSH2 by FOXO3a. FOXO3a overexpression in MEF cells and tet-on flag-h-FOXO3a transgenic mouse exhibited high resistance to gamma radiation. Small intestine showed less damage and apoptosis in doxycycline-treated mice. The median and maximum lifespan of the doxycycline-treated transgenic mice increased by about 30%. The results suggest that FOXO3a overexpression provide protection against gamma radiation and lifespan extension possibly via activation of DNA repair.

Senescence is a multifactorial and individualised process of age-related physiological decline. Cellular markers, such as telomere length and DNA methylation, can reveal subtle changes associated with chronological age or expected lifespan. In this study, we evaluated the utility of fin tissue as a surrogate for assessing telomere length and proportion of DNA methylation in the gonads of a small, short-lived laboratory fish, the turquoise killifish (Nothobranchius furzeri). We collected fin and gonadal tissues from both females and males at three different ages. We extracted DNA to measure telomere length via terminal restriction fragment (TRF) analysis and global DNA methylation levels using double-digest restriction-associated DNA sequencing (ddRADseq). Our results show a notable correspondence between telomere length and DNA methylation patterns in fin and gonadal tissues. These findings support the use of fin biopsies as a non-lethal method for assessing ageing biomarkers in the gonads of small freshwater fish.

Emerging evidence has revealed a strong association between obstructive sleep apnea (OSA) and aging. Considering the critical role of the cardiovascular system, this review explores the key mechanisms linking OSA to cardiovascular aging through a focus on chronic intermittent hypoxia (CIH) -induced oxidative stress and chronic inflammation. Specifically, we examine six key pathways: (1) cellular senescence, (2) mitochondrial dysfunction, (3) metabolic dysregulation, (4) telomere attrition, (5) impaired intercellular communication, and (6) adipose tissue senescence. These insights provide a foundation for identifying novel interventions and therapeutic targets to mitigate or even reverse cardiovascular aging.

Age-related renal impairment often occurs insidiously and has become an important cause of chronic renal failure, especially when individuals with other chronic diseases. However, there is lack of effective treatments. Research on diabetic patients has revealed that empagliflozin (EMPA), one of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, exhibits a distinct protective effect on aging kidneys. EMPA has been shown to improve renal fibrosis and ameliorate inflammatory cytokines, including IL-1 and IL-8, which are closely associated with the aging process in db/db mouse models. As a result, we assessed markers indicative of kidney senescence P16 and senescence-associated β-galactosidase (SA-β-gal) in the renal tissue of male C57 mice undergoing natural aging, following treatment with EMPA. Our findings showed that in Old-EMPA group, the expression of P16 and SA-β-gal were downregulated compared to Old-vehicle group, while these markers were expressed lower in Young group. RNA sequencing analysis indicated that our findings correlated with increased expressions of Six1 and Wnt4 in the kidney. Protein-protein interaction (PPI) analysis confirmed an interaction between Six1 and Wnt4. After treatment with EMPA, the expression of Six1 and Wnt4 was observed to increase in both aging Primary renal tubular epithelial cells (PRTECs) and HK-2 cells, whereas the expression of NF-κB and its downstream effectors IL-1β and TNF-α decreased, leading to an improvement in aging-related changes.

Current knowledge regarding the role of gut microbiota (GM) dysbiosis and biological aging in the pathogenesis of age-related macular degeneration (AMD) remains limited. This study aims to explore the causal relationships among these factors in AMD development. Utilizing two-sample bidirectional mendelian randomization (MR), we analyzed genome-wide association study (GWAS) data from 105,248 individuals, including 14,034 early AMD cases, to assess causality between AMD, GM taxa, and biological aging phenotypes such as epigenetic clocks, telomere length, mitochondrial DNA copy number, immune cell traits, and inflammatory proteins. Multivariable MR (MVMR) was employed to evaluate mediation pathways, complemented by sensitivity analyses to ensure robustness. We identified 8 causal GM taxa (including one phylum, one class, one order, one family, and four species) along with 8 GM functional pathways. Additionally, 78 immune cell traits, 3 circulating inflammatory proteins, and DNA methylation PhenoAge acceleration were identified as causal biological aging phenotypes linked to AMD. Mediation analysis revealed three pathways connecting GM functional pathways, immune cell traits, and AMD. Reverse MR analysis highlighted the modifying effects of AMD on GM and other aging phenotypes. This study represents a pioneering effort to identify causal GM taxa associated with the onset of AMD and to unravel potential mechanisms from the perspective of biological aging, providing genetic insights into the connections among gut microbiota, immune cell traits, and AMD.

Induced pluripotent stem cells (iPSCs) derived from patients with premature aging disorders are widely regarded as a foundation for both the study of fundamental aging mechanisms and preclinical testing of anti-aging therapies. The most well-studied is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a lamin A gene mutation. Comparing the progeroid phenotype in cell models of distinct premature aging syndromes is critical for identifying early and common aging hallmarks. In this study, using a non-integrative episomal approach we reprogrammed iPSCs from cells of a patient suffering from Wiedemann-Rautenstrauch Syndrome (WRS), which is caused by bi-allelic pathogenic mutations of the RNA polymerase III subunit A gene (POLR3A). In parallel, an iPSC line with the classic HGPS caused by a lamin A mutation was obtained. HGPS and WRS patient fibroblasts showed similar signs of cellular aging; however, unlike HGPS, the causal link between the premature aging phenotype and WRS driving mutations is unclear. RNA polymerase III is required for the transcription of small nuclear RNAs and being a target of TORC1 (Target of Rapamycin kinase Complex 1), it plays a role in longevity and aging in model organisms. Whereas lamin A is downregulated in iPSCs, allowing for regeneration of HGPS iPSCs, we found that POLR3A is upregulated during reprogramming. Enhanced expression of mutant POLR3A in WRS iPSCs led to nucleolus abnormalities and telomerase RNA component (TERC) sequestration in the nucleoli in WRS iPSCs. WRS iPSCs may be an important model for developing new therapeutic approaches affecting premature aging of stem cells.

Extracellular vesicles present a promising alternative to stem cells in regenerative medicine and gerontology. They offer significant advantages over cell transplantation, demonstrating potential for slowing aging and treating age-related diseases. Extracellular vesicles secreted by diverse cell types modulate inflammation, stimulate tissue regeneration, and exhibit anti-inflammatory and immunomodulatory properties. This work explores the therapeutic potential of extracellular vesicles as alternatives to cell therapy, examining their key advantages and current limitations. It specifically focuses on their roles within established aging mechanisms and their dual utility as biomarkers and therapeutic agents. Critical aspects of extracellular vesicle translation are addressed, including standardized methods for production, storage stability optimization, and engineering strategies for cargo loading and targeting. Extracellular vesicles possess unique biological properties-inherent biocompatibility, low immunogenicity, ability to cross biological barriers, and high biological activity at low doses. Preclinical studies across various age-related pathologies (neurodegeneration, cardiovascular disease, sarcopenia) consistently report efficacy in reducing inflammation, promoting tissue repair, and improving functional outcomes. These findings strongly support the capacity of extracellular vesicles to mimic many therapeutic effects of parental cells while mitigating risks like tumorigenicity or immunorejection associated with whole-cell therapies. Overcoming challenges in scalable manufacturing, quality control, regulatory standardization, and targeted delivery is essential for the clinical translation of extracellular vesicles. Despite these hurdles, their compelling preclinical evidence and inherent advantages position them as a major future direction. They are expected to play a key role in combating age-related decline and advancing regenerative medicine, becoming a cornerstone of next-generation biomedical interventions over the next decade.

Phytochemicals represent emerging anti-aging therapeutic candidates, with Marchantia polymorpha L. (liverwort) gaining significant attention due to its broad-spectrum pharmacological properties. This plant exhibits remarkable wound-healing and regenerative capabilities, making it a promising candidate for the development of modern anti-aging drugs. In the presented study, 12-ethoxy-Marchantin A (EMA), a new macrocyclic bis-bibenzyl compound, was isolated and identified from M. polymorpha. Using a Lipopolysaccharide (LPS)-induced mouse macrophage RAW264.7 macrophage model, a Caenorhabditis elegans (C. elegans) aging model, and network pharmacology analysis, we systematically investigated the pharmacological mechanisms underlying its anti-aging effects. Our results demonstrated that EMA significantly reduced inflammatory cytokines and nitric oxide (NO) in LPS-stimulated RAW264.7 cells via the nuclear factor erythroid 2-related factor 2 (Nrf2) / heme oxygenase (HO-1) pathway. Mechanistically, EMA triggered a reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK)-dependent Nrf2 antioxidant signaling cascade. EMA significantly extended the lifespan and enhanced fecundity in the N2 strain of C. elegans, while reducing lipofuscin deposition and ROS levels. Additionally, EMA enhanced oxidative and heat stress resistance in the N2 strain of C. elegans. Network pharmacology revealed that its anti-aging effects may be mediated by MAPKs/Nrf2/HO-1 pathway regulation. Collectively, these findings highlight EMA as a potent anti-aging with therapeutic potential for aging-related conditions.