Biogerontology最新文献

Isotschimgine (ITG) is a bornane-type monoterpenoid derivative naturally occurring in genus Ferula plants and propolis. Its effects on aging and the underlying mechanisms are not yet well understood. This study employed Caenorhabditis elegans (C. elegans) as a model organism to evaluate the potential of ITG in extending lifespan, enhancing healthspan, and promoting neuroprotection, while exploring the underlying mechanisms involved. The results showed that ITG extended the lifespan and healthspan of C. elegans, significantly enhanced stress resistance and detoxification functions. Studies on mutants and qPCR data indicated that ITG-mediated lifespan extension was modulated by the insulin/IGF-1 signaling pathway and nuclear hormone receptors. Furthermore, ITG markedly increased stress-responsive genes, including daf-16 and its downstream genes sod-3 and hsp-16.2, as well as NHR downstream detoxification-related genes cyp35a1, cyp35b3, cyp35c1, gst-4, pgp-3 and pgp-13. Additionally, ITG alleviated β-amyloid-induced paralysis and behavioral dysfunction in transgenic C. elegans strains. The neuroprotective efficacy of ITG was weakened by RNAi knockdown of nuclear hormone receptors daf-12 and nhr-8. Overall, our study identifies ITG as a potential compound for promoting longevity and neuroprotection, mediated through nuclear hormone receptors.

Ageing is generally regarded as a non-adaptive by-product of evolution. Based on this premise three classic evolutionary theories of ageing have been proposed. These theories have dominated the literature for several decades. Despite their individual nuances, the common thread which unites them is that they posit that ageing results from a decline in the intensity of natural selection with chronological age. Empirical evidence has been identified which supports each theory. However, a consensus remains to be fully established as to which theory best accounts for the evolution of ageing. A consequence of this uncertainty are counter arguments which advocate for alternative theoretical frameworks, such as those which propose an adaptive origin for ageing, senescence, or death. Given this backdrop, this review has several aims. Firstly, to briefly discuss the classic evolutionary theories. Secondly, to evaluate how evolutionary forces beyond a monotonic decrease in natural selection can affect the evolution of ageing. Thirdly, to examine alternatives to the classic theories. Finally, to introduce a pluralistic interpretation of the evolution of ageing. The basis of this pluralistic theoretical framework is the recognition that certain evolutionary ideas will be more appropriate depending on the organism, its ecological context, and its life history.

Finding interventions to break the trade-off between reproduction and lifespan can provide insight into physiological limitations of animals. Effects of dietary protein quality on the trade-off are currently unclear, but clarity could lead to better designed diets that match animal needs. Dietary amino acid blends matching yolk proteins support reproduction and extend lifespan in fruit flies. To test if this is conserved across species, we matched dietary amino acids to vitellogenin to test reproduction and lifespan in adult females of the lubber grasshopper. Specifically, we compared varying degrees of protein quality by manipulating dietary essential amino acids. We identified a high-quality protein diet (amino acids matched to vitellogenin, or reproductive needs) that increased reproduction and matched lifespan in comparison to diets that differed only in the ratios of essential amino acids (i.e., were isocaloric and isonitrogenous). All these diets had longer lifespan but lower reproductive output than fully fed controls. In a separate experiment, full reproduction was possible on the high-quality artificial diet when offered at a 78% higher protein quantity and with a larger lettuce supplement (~ 17% of ad libitum). Additionally, we observed that as dietary protein quality was decreased (i.e., diets were less matched to vitellogenin), reproduction was reduced, and lifespan was extended in the more extreme scenarios. Taken together, these results indicate that the balance of dietary essential amino acids plays an important role in the lifespan and reproduction trade-off, while more work needs to be conducted to find the optimal diet mix for this species.

The iron-sulfur domain (CISD) proteins of CDGSH are classified into three classes: CISD1, CISD2, and CISD3. During premature ageing, mutations that affect these proteins, namely their binding sites, could result in reduced protein production and an inability to preserve cellular integrity. Consequently, this leads to the development of conditions such as diabetes. Notably, CISD3 plays a crucial role in the management of age-related disorders such as Wolfram syndrome, which is often referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Computational analyses have predicted that CISD3 regulates the redox state, safeguards the endoplasmic reticulum and mitochondria, and maintains intracellular calcium levels. CISD3, a member of a recently discovered gene family associated with the CDGSH iron protein apoptotic compensatory response, fulfils a crucial function in mitigating the effects of accelerated ageing. The compound "(-)-(2S)-7,4'-Dihydroxyflavanone" has been discovered by computational drug design as a possible activator of CISD3. It shows potential therapeutic benefits in ameliorating metabolic dysfunction and enhancing glucose regulation. The ligand binds to the binding pocket of the CISD3 protein, increasing the stability of the protein and enhancing its functionality. The current research investigates the binding processes of the molecule in various structures and its anticipated effects on these tissues, therefore providing valuable insights into the mitigation of age-related diabetes and metabolic dysfunction. The projected tripling of the worldwide population of individuals aged 50 and above by 2050 necessitates the urgent development of immunoinformatics-based approaches, including pharmaceutical therapies that target CISD3, to prevent age-related pathologies. The stimulation of CISD3, namely by compounds such as "(-)-(2S)-7,4'-Dihydroxyflavanone", has the potential to counteract telomere shortening and improve metabolic pathways.

The integumentary system serves as a crucial protective barrier and is subject to complex signaling pathways that regulate its physiological functions. As the body's first line of defense, the skin is continuously exposed to environmental stressors, necessitating a robust network of signaling molecules to maintain homeostasis. Considering the main cellular components to be keratinocytes, melanocytes, fibroblasts, and fibrous components, collagen of various types, this review explores the intricate signaling mechanisms that govern skin integrity, focusing on key pathways involved in impacts of ageing and environment factors on skin health. The role of growth factors, cytokines, hormones and other molecular mediators in these processes is examined. Specially for women, decrease of estrogen is determinant to alter signaling and to compromise skin structure, especially the dermis. Environmental factors, such as ultraviolet rays and pollution alongside the impact of ageing on signaling pathways, especially TGF-β and proteases (metalloproteinases and cathepsins). Furthermore, with advancing age, the skin's capacity to shelter microbiome challenges diminishes, leading to alterations in signal transduction and subsequent functional decline. Understanding these age-related changes is essential for developing targeted therapies aimed at enhancing skin health and resilience, but also offers a promising avenue for the treatment of skin disorders and the promotion of healthy ageing.

The early-life gut microbiota (GM) is increasingly recognized for its contributions to human health and disease over time. Microbiota composition, influenced by factors like race, geography, lifestyle, and individual differences, is subject to change. The GM serves dual roles, defending against pathogens and shaping the host immune system. Disruptions in microbial composition can lead to immune dysregulation, impacting defense mechanisms. Additionally, GM aids digestion, releasing nutrients and influencing physiological systems like the liver, brain, and endocrine system through microbial metabolites. Dysbiosis disrupts intestinal homeostasis, contributing to age-related diseases. Recent studies are elucidating the bacterial species that characterize a healthy microbiota, defining what constitutes a 'healthy' colonic microbiota. The present review article focuses on the importance of microbiome composition for the development of homeostasis and the roles of GM during aging and the age-related diseases caused by the alteration in gut microbial communities. This article might also help the readers to find treatments targeting GM for the prevention of various diseases linked to it effectively.

The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues. Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8⁺ T and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8⁺ T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors. Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.

Despite frequent claims regarding radical extensions of human lifespan in the near future, many pragmatic scientists caution against excessive and baseless optimism on this front. In this study, we examine the compensation effect of mortality (CEM) as a potential challenge to substantial lifespan extension. The CEM is an empirical mortality regularity, often depicted as relative mortality convergence at advanced ages. Analysis of mortality data from 44 human populations, available in the Human Mortality Database, demonstrated that CEM can be represented as a continuous decline in relative mortality variation (assessed through the coefficient of variation and the standard deviation of the logarithm of mortality) with age, reaching a minimum corresponding to the species-specific lifespan. Through this method, the species-specific lifespan is determined to be 96-97 years, closely aligning with estimates derived from correlations between Gompertz parameters (95-98 years). Importantly, this representation of CEM can be achieved non-parametrically, eliminating the need for estimating Gompertz parameters. CEM is a challenge to lifespan extension, because it suggests that the true aging rate in humans (based on loss of vital elements, e.g., functional cells) remains stable at approximately 1% per year in the majority of human populations and is not affected by environmental or familial longevity factors. Given this rate of functional cell loss, one might anticipate that the total pool of functional cells could be entirely depleted by the age of 115-120 years creating physiological limit to human lifespan. Mortality pattern of supercentenarians (110 + years) aligns with this prediction.

Peritoneal immune cell function is a reliable indicator of aging and longevity in mice and inflammaging is associated with a shorter lifespan. Nevertheless, it is unknown if the content of cytokines in these immune cells is linked to individual differences in lifespan. Therefore, this work aimed to investigate different peritoneal leukocyte populations and their content in intracellular pro-inflammatory (TNF and IL-6) and anti-inflammatory (IL-10) cytokines by flow cytometry in adult (10 months-old, n = 8) and old (18 months-old, n = 20) female Swiss/ICR mice. In addition, old mice were monitored longitudinally throughout their aging process, and the same markers were analyzed at the very old (24 months-old, n = 8) and long-lived (30 months-old, n = 4) ages. The longitudinal follow-up allowed us to relate the investigated parameters to individual lifespans. The results show that long-lived female mice exhibit an adult-like profile in most parameters investigated but also display specific immune adaptations, such as increased CD4+ and CD8+ T cells containing the pro-inflammatory TNF cytokine and CD4+ T cells and macrophages containing the anti-inflammatory cytokine IL-10. These adaptations may underlie their exceptional longevity. In addition, a negative correlation was obtained between the percentage of cytotoxic T cells, KLRG-1/CD4, large peritoneal macrophages, and the percentage of CD4+ T cells containing IL-6 and macrophages containing IL-10 in old age and lifespan, whereas a positive correlation was found between the CD4/CD8 ratio and the longevity of the animals at the same age. These results highlight the crucial role of peritoneal leukocytes in inflammaging and longevity.

The aging process demonstrates notable differences between males and females, which are key factors in disease susceptibility and lifespan. The differences in sex chromosomes are fundamental to the presence of sex bias in organisms. Moreover, sex-specific epigenetic modifications and changes in sex hormone levels impact the development of immunity differently during embryonic development and beyond. Mitochondria, telomeres, homeodynamic space, and intestinal flora are intricately connected to sex differences in aging. These elements can have diverse effects on men and women, resulting in unique biological transformations and health outcomes as they grow older. This review explores how sex interacts with these elements and shapes the aging process.