Search Results (15)

Autophagy is an evolutionarily preserved intracellular degradation process pivotal in maintaining proteostasis, mitochondrial homeostasis, and metabolic equilibrium, all of which are dysregulated with aging. Aberrant autophagy has been recognized as a hallmark of human aging and age-related diseases, including neurodegeneration, metabolic dysfunction, cardiovascular diseases, and cancer. Bioactive natural compounds derived from plants, foods, and marine organisms have emerged as potent modulators of autophagy, offering a promising strategy to counteract aging and promote healthy lifespan. Mechanistically, these compounds regulate autophagy by modulating key signaling pathways, such as AMPK, PI3K/AKT/mTOR, SIRT1, and FOXO, while also alleviating oxidative stress, inflammation, and mitochondrial dysfunction. Natural compounds like polyphenols, flavonoids, alkaloids, terpenoids, and carotenoids exhibit dual roles by restoring age-related suppressed autophagic flux and inhibiting excessive autophagy-induced cell death. In this review, we provide a comprehensive overview of the molecular mechanisms through which bioactive natural compounds modulate autophagy and impact human aging and longevity. We discuss both experimental and clinical evidence supporting their geroprotective effects, limitations regarding bioavailability and dose-dependent effects, and prospects for the utilization of autophagy-targeting natural products in aging intervention strategies. Full article

Preeclampsia (PE) has traditionally been regarded as a pregnancy-limited hypertensive disorder; however, accumulating evidence increasingly positions it as a pivotal early-life vascular stress test that manifests underlying vulnerabilities and accelerates biological aging. Women with a history of PE exhibit a heightened susceptibility to premature-onset multi-systemic diseases, specifically cardiovascular, ovarian, renal, and metabolic decline. This suggests that PE acts as a catalyst for accelerated aging, driven by shared pathophysiological pathways that represent common mechanisms of systemic senescence. This review provides a comprehensive analysis of the epidemiological links and pathogenic drivers underpinning accelerated systemic aging following PE, with a specific focus on the cardiovascular-ovarian axis. Epidemiological data consistently demonstrate that women with prior PE exhibit significantly reduced anti-Müllerian hormone (AMH) levels, translating to an estimated 1.5-year acceleration in reproductive aging. In parallel, PE is associated with a twofold increase in lifetime cardiovascular disease (CVD) risk and the onset of chronic hypertension occurring an average of 7.7 years earlier. However, reconciling the phenotypic heterogeneity of PE and transcending the constraints of non-experimental designs are essential for firmly establishing this accelerated aging paradigm. At the molecular level, PE and ovarian aging converge on shared pathways—including mitochondrial dysfunction, oxidative stress, inflammation, and epigenetic dysregulation—collectively defining a distinct pathogenic ovarian–vascular aging axis. Proposed geroscience-based strategies advocate for refined risk stratification by incorporating molecular aging biomarkers—such as epigenetic clocks and inflammatory profiles—alongside conventional clinical indicators. This integrative framework facilitates the early identification of high-risk aging phenotypes, enabling targeted monitoring and timely interventions to preemptively modulate accelerated aging pathways. Pharmacological approaches within this framework emphasize the judicious repurposing of established agents, such as metformin, statins, and SGLT2 inhibitors, while emerging gerotherapeutics, including senolytics and senomorphics, provide a conceptual foundation for targeting the fundamental biological drivers of senescence. Although these geroprotective strategies, including the repurposing of established agents and the use of senolytics, offer innovative conceptual frameworks for targeting the fundamental drivers of senescence, they remain largely exploratory and require further clinical validation. Such strategies offer novel opportunities to shift the clinical focus from treating isolated comorbidities to modulating the shared molecular substrates of aging, ultimately promoting healthy aging and functional longevity in the elderly female population. Full article

Metformin is a first-line oral antidiabetic agent that has attracted increasing interest as a potential geroprotective therapy due to its ability to improve metabolic homeostasis, reduce oxidative stress, and attenuate chronic inflammation. However, its role in skeletal muscle aging and sarcopenia remains controversial. Observational and epidemiological studies suggest that metformin use is associated with a lower prevalence of sarcopenia, particularly in metabolically compromised or insulin-resistant older populations, where improvements in systemic metabolism and inflammatory burden may indirectly support muscle quality and function. In contrast, randomized interventional trials in metabolically healthy older adults indicate that metformin can blunt resistance exercise–induced muscle hypertrophy and protein synthesis, likely through sustained activation of AMP-activated protein kinase (AMPK) and consequent suppression of mammalian target of rapamycin complex 1 (mTORC1) signaling. This perspective argues that these apparently opposing outcomes reflect a con-text-dependent therapeutic paradox rather than inconsistent evidence. Metformin may provide metabolic protection in frail, insulin-resistant individuals, yet limit anabolic adaptations in physically active older adults. These findings emphasize the necessity for precision geropharmacological strategies to balance metabolic longevity with preservation of musculoskeletal health in aging populations. Full article

Elderly individuals are more vulnerable to disease due to their increased frailty. Emerging evidence highlights the potential of probiotics as geroprotective agents by maintaining gut health and modulating key physiological processes involved in aging, such as inflammation, cognitive functions, and metabolism. Here, we investigated the geroprotective potential of four probiotic strains (Lacticaseibacillus paracasei LPC1114, Limosilactobacillus reuteri PBS072, Bifidobacterium breve BB077, and Bifidobacterium animalis subsp. lactis BL050) using Caenorhabditis elegans as an aging model. Mid-life healthspan parameters were assessed, including lifespan, motility, ROS levels, lipofuscin accumulation, and cognitive capabilities. The probiotics exhibited strain-specific effects. L. reuteri PBS072 and B. lactis BL050 significantly increased locomotion by 20% and decreased ROS levels by 70% and 30% respectively, suggesting enhanced oxidative stress response and neuromuscular maintenance. B. breve BB077, L. paracasei LPC1114, and L. reuteri PBS072 enhanced associative learning performance, whereas B. lactis BL050 improved chemotactic response. Notably, only L. paracasei LPC1114 and L. reuteri PBS072 extended the maximum lifespan by 4 and 5 days, respectively, an effect mediated by the longevity-related genes skn1, sir2.1, and daf16. Our findings highlight the multifaceted, strain-specific geroprotective properties of probiotics and support their potential as microbiome-based interventions to promote healthy aging. Full article

Ovarian aging is characterized by a gradual decline in both reproductive and endocrine functions, ultimately culminating in the cessation of ovarian activity around the age of 50, when most women experience natural menopause. The decline begins early, as follicular attrition is initiated in utero and continues throughout childhood and reproductive life. Most follicles undergo atresia without progressing through substantial stages of growth. With increasing age, a pronounced reduction occurs in the population of resting follicles within the ovarian reserve, accompanied by a decline in the size of growing follicular cohorts. Around the age of 38, the rate of follicular depletion accelerates, sometimes resulting in diminished ovarian reserve (DOR). The subsequent menopausal transition involves complex, irregular hormonal dynamics, manifesting as increasingly erratic menstrual patterns, primarily driven by fluctuations in circulating estrogens and a rising incidence of anovulatory cycles. In parallel with the progressive depletion of the follicular pool, the serum concentrations of anti-Müllerian hormone (AMH) decline gradually, while reductions in inhibin B levels become more apparent during the late reproductive years. The concomitant decline in both inhibin B and estrogen levels leads to a compensatory rise in circulating follicle-stimulating hormone (FSH) concentrations. Together, these endocrine changes, alongside the eventual exhaustion of the follicular reserve, converge in the onset of menopause, which is defined by the absence of menstruation for twelve consecutive months. The mechanisms contributing to ovarian aging are complex and multifactorial, involving both the oocyte and the somatic cells within the follicular microenvironment. Oxidative stress is thought to play a central role in the age-related decline in oocyte quality, primarily through its harmful effects on mitochondrial DNA integrity and broader aspects of cellular function. Although granulosa cells appear to be relatively more resilient, they are not exempt from age-associated damage, which may impair their hormonal activity and, given their close functional relationship with the oocyte, negatively influence oocyte competence. In addition, histological changes in the ovarian stroma, such as fibrosis and heightened inflammatory responses, are believed to further contribute to the progressive deterioration of ovarian function. A deeper understanding of the biological processes driving ovarian aging has facilitated the development of experimental interventions aimed at extending ovarian functionality. Among these are the autologous transfer of mitochondria and stem cell-based therapies, including the use of exosome-producing cells. Additional approaches involve targeting longevity pathways, such as those modulated by caloric restriction, or employing pharmacological agents with geroprotective properties. While these strategies are supported by compelling experimental data, robust clinical evidence in humans remains limited. Full article

Dermal fibroblasts, the primary stromal cells of the dermis, exhibit remarkable plasticity in response to various stimuli, playing crucial roles in tissue homeostasis, wound healing, and ECM production. This study examines the molecular mechanisms underlying fibroblast plasticity, including key signaling pathways, epigenetic regulation, and microRNA-mediated control. The impact of aging on ECM synthesis and remodeling is discussed, and the diminished production of vital components such as collagen, elastin, and glycosaminoglycans are highlighted, alongside enhanced ECM degradation through upregulated matrix metalloproteinase activity and accumulation of advanced glycation end products. The process of cellular senescence in dermal fibroblasts is explored, with its role in skin aging and its effects on tissue homeostasis and repair capacity being highlighted. The senescence-associated secretory phenotype (SASP) is examined for its contribution to chronic inflammation and ECM disruption. This review also presents therapeutic perspectives, focusing on senolytics and geroprotectors as promising strategies to combat the negative effects of fibroblast senescence. Current challenges in translating preclinical findings to human therapies are addressed, along with future directions for research in this field. This comprehensive review explores the complex interplay between dermal fibroblast plasticity, cellular senescence, and extracellular matrix (ECM) remodeling in the context of skin aging. In conclusion, understanding the complex interplay between dermal fibroblast plasticity, cellular senescence, and extracellular matrix (ECM) remodeling is essential for developing effective anti-aging interventions, which highlights the need for further research into senolytic and geroprotective therapies to enhance skin health and longevity. This approach has shown promising results in preclinical studies, demonstrating improved skin elasticity and reduced signs of aging. Full article

Aging is a process of gradual functional decline in complex physiological systems and is closely related to the occurrence of various diseases. Berberine, a bioactive alkaloid derived from Coptis chinensis (Huanglian), has emerged as a promising candidate for anti-aging interventions. This study comprehensively investigated the lifespan-extending effects and molecular mechanisms of berberine in C. elegans through integrated approaches including lifespan assays, locomotor activity analysis, oxidative stress challenges, and transcriptomic profiling. Furthermore, genetic models of mutant and transgenic worms were employed to delineate their interactions with the insulin/IGF-1 signaling (IIS) pathway. Our results demonstrate that berberine extended the mean lifespan of wild-type worms by 27%. By activating transcription factors such as DAF-16/FOXO, HSF-1, and SKN-1/NRF2, berberine upregulated antioxidant enzyme expression, reduced lipofuscin accumulation, and improved stress resistance. Transcriptomic analysis revealed significant changes in lipid metabolism-related genes, particularly in pathways involving fatty acid synthesis, degradation, and sphingolipid metabolism. These findings establish that berberine exerts multi-target anti-aging effects through coordinated activation of stress-responsive pathways and metabolic optimization, providing mechanistic insights for developing natural product-based geroprotective strategies. Full article

Aging presents an increasingly significant challenge globally, driven by the growing proportion of individuals aged 60 and older. Currently, there is substantial research interest in pro-longevity interventions that target pivotal signaling pathways, aiming not only to extend lifespan but also to enhance healthspan. One particularly promising approach involves inducing a hormetic response through the utilization of natural compounds defined as hormetins. Various studies have introduced the flavonoid icariin as beneficial for age-related diseases such as cardiovascular and neurodegenerative conditions. To validate its potential pro-longevity properties, we employed Caenorhabditis elegans as an experimental platform. The accumulated results suggest that icariin extends the lifespan of C. elegans through modulation of the DAF-2, corresponding to the insulin/IGF-1 signaling pathway in humans. Additionally, we identified increased resistance to heat and oxidative stress, modulation of lipid metabolism, improved late-life healthspan, and an extended lifespan upon icariin treatment. Consequently, a model mechanism of action was provided for icariin that involves the modulation of various players within the stress-response network. Collectively, the obtained data reveal that icariin is a potential hormetic agent with geroprotective properties that merits future developments. Full article

Aging is characterized by alterations in the inflammatory microenvironment, which is tightly regulated by a complex network of inflammatory mediators. Excessive calorie consumption contributes to age- and lifestyle-associated diseases like obesity, type 2 diabetes, cardiovascular disorders, and cancer, while limited nutrient availability may lead to systemic health-promoting adaptations. Geroprotective effects of short-term caloric restriction (CR) can beneficially regulate innate immune receptors and interferon signaling in the liver of aged mice, but how CR impacts the hepatic release of immunomodulatory mediators like cytokines and lipid mediators (LM) is elusive. Here, we investigated the impact of aging on the inflammatory microenvironment in the liver and its linkage to calorie consumption. The livers of female young and aged C57BL/6JRj mice, as well as of aged mice after caloric restriction (CR) up to 28 days, with and without subsequent re-feeding (2 days), were evaluated. Surprisingly, despite differences in the hepatic proteome of young and old mice, aging did not promote a pro-inflammatory environment in the liver, but it reduced lipoxygenase-mediated formation of LM from polyunsaturated fatty acids without affecting the expression of the involved lipoxygenases and related oxygenases. Moreover, CR failed to ameliorate the secretion of pro-inflammatory cytokines but shifted the LM production to the formation of monohydroxylated LM with inflammation-resolving features. Unexpectedly, re-feeding after CR even further decreased the inflammatory response as LM species were markedly downregulated. Our findings raise the question of how short-term CR is indeed beneficial as a nutritional intervention for healthy elderly subjects and further stress the necessity to address tissue-specific inflammatory states. Full article

Disrupted biological function, manifesting through the hallmarks of aging, poses one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease in nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds, to restore NAD+ levels present in youth. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through the inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NAD+ precursor supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans. Full article

Globally, better health care access and social conditions ensured a significant increase in the life expectancy of the population. There is, however, a clear increase in the incidence of age-related diseases which, besides affecting the social and economic sustainability of countries and regions around the globe, leads to a decrease in the individual’s quality of life. There is an urgent need for interventions that can reverse, or at least prevent and delay, the age-associated pathological deterioration. Within this line, this narrative review aims to assess updated evidence that explores the potential therapeutic targets that can mimic or complement the recognized anti-aging effects of physical exercise. We considered pertinent to review the anti-aging effects of the following drugs and supplements: Rapamycin and Rapamycin analogues (Rapalogs); Metformin; 2-deoxy-D-glucose; Somatostatin analogues; Pegvisomant; Trametinib; Spermidine; Fisetin; Quercetin; Navitoclax; TA-65; Resveratrol; Melatonin; Curcumin; Rhodiola rosea and Caffeine. The current scientific evidence on the anti-aging effect of these drugs and supplements is still scarce and no recommendation of their generalized use can be made at this stage. Further studies are warranted to determine which therapies display a geroprotective effect and are capable of emulating the benefits of physical exercise. Full article

Population aging is one of the largest challenges of the 21st century. As more people live to advanced ages, the prevalence of age-related diseases and disabilities will increase placing an ever larger burden on our healthcare system. A potential solution to this conundrum is to develop treatments that prevent, delay or reduce the severity of age-related diseases by decreasing the rate of the aging process. This ambition has been accomplished in model organisms through dietary, genetic and pharmacological interventions. The pharmacological approaches hold the greatest opportunity for successful translation to the clinic. The discovery of such pharmacological interventions in aging requires high-throughput screening strategies. However, the majority of screens performed for geroprotective drugs in C. elegans so far are rather low throughput. Therefore, the development of high-throughput screening strategies is of utmost importance. Full article

Mitochondria are intracellular organelles involved in a myriad of activities. To safeguard their vital functions, mitochondrial quality control (MQC) systems are in place to support organelle plasticity as well as physical and functional connections with other cellular compartments. In particular, mitochondrial interactions with the endosomal compartment support the shuttle of ions and metabolites across organelles, while those with lysosomes ensure the recycling of obsolete materials. The extrusion of mitochondrial components via the generation and release of mitochondrial-derived vesicles (MDVs) has recently been described. MDV trafficking is now included among MQC pathways, possibly operating via mitochondrial–lysosomal contacts. Since mitochondrial dysfunction is acknowledged as a hallmark of aging and a major pathogenic factor of multiple age-associated conditions, the analysis of MDVs and, more generally, of extracellular vesicles (EVs) is recognized as a valuable research tool. The dissection of EV trafficking may help unravel new pathophysiological pathways of aging and diseases as well as novel biomarkers to be used in research and clinical settings. Here, we discuss (1) MQC pathways with a focus on mitophagy and MDV generation; (2) changes of MQC pathways during aging and their contribution to inflamm-aging and progeroid conditions; and (3) the relevance of MQC failure to several disorders, including neurodegenerative conditions (i.e., Parkinson’s disease, Alzheimer’s disease) and cardiovascular disease. Full article

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca²⁺ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson’s disease as a prototypical geroscience condition. Full article

In the elderly, whole-body health largely relies on healthy skeletal muscle, which controls body stability, locomotion, and metabolic homeostasis. Age-related skeletal muscle structural/functional deterioration is associated with a higher risk of severe comorbid conditions and poorer outcomes, demanding major socioeconomic costs. Thus, the need for efficient so-called geroprotective strategies to improve resilience and ensure a good quality of life in older subjects is urgent. Skeletal muscle senescence and metabolic dysregulation share common cellular/intracellular mechanisms, potentially representing targets for intervention to preserve muscle integrity. Many factors converge in aging, and multifaceted approaches have been proposed as interventions, although they have often been inconclusive. Physical exercise can counteract aging and metabolic deficits, not only in maintaining tissue mass, but also by preserving tissue secretory function. Indeed, skeletal muscle is currently considered a proper secretory organ controlling distant organ functions through immunoactive regulatory small peptides called myokines. This review provides a current perspective on the main biomolecular mechanisms underlying age-dependent and metabolic deterioration of skeletal muscle, herein discussed as a secretory organ, the functional integrity of which largely depends on exercise and myokine release. In particular, muscle-derived interleukin (IL)-6 is discussed as a nutrient-level biosensor. Overall, exercise and vitamin D are addressed as optimal geroprotective strategies in view of their multi-target effects. Full article