Microbiome and Human Aging: Probiotic and Prebiotic Potentials in Longevity, Skin Health and Cellular Senescence

The role of the microbiome in human aging is important: the microbiome directly impacts aging through the gastrointestinal system. However, the microbial impact on skin has yet to be fully understood. For example, cellular senescence is an intrinsic aging process that has been recently associated with microbial imbalance. With age, cells become senescent in response to stress wherein they undergo irreversible growth arrest while maintaining high metabolic activity. An accumulation of senescent cells has been linked to various aging and chronic pathologies due to an overexpression of the senescence-associated secretory phenotype (SASP) comprised of proinflammatory cytokines, chemokines, growth factors, proteases, lipids and extracellular matrix components. In particular, dermatological disorders may be promoted by senescence as the skin is a common site of accumulation. The gut microbiota influences cellular senescence and skin disruption through the gut-skin axis and secretion of microbial metabolites. Metabolomics can be used to identify and quantify metabolites involved in senescence. Moreover, novel anti-senescent therapeutics are warranted given the poor safety profiles of current pharmaceutical drugs. Probiotics and prebiotics may be effective alternatives, considering the relationship between the microbiome and healthy aging. However, further research on gut composition under a senescent status is needed to develop immunomodulatory therapies.

New Aspects in Metabolism of Aging

In recent years there has been a renewed emphasis on metabolism as a key contributor to a host of chronic non-communicable conditions: cancer, neurodegeneration, frailty, and functional declines in immune and inflammatory processes. All share a common connection in metabolic dysfunction. Furthermore, aging itself is associated with changes in metabolism, although the underlying drivers for these changes are unknown. Here we introduce speakers working at the cutting edge in metabolism research, and whose studies are of direct relevance to aging. Dr. Chandel will focus on mitochondrial biology, describing recent advances in understanding the mechanisms of the beneficial effects of metformin. Dr. Haigis takes the mitochondrial theme to cancer biology, the area of research that revived metabolic perspectives in biomedical research. Dr. Najt’s talk describes a less well studied organelle, the lipid droplet, and its role in a rapidly expanding area of research on lipid metabolic regulation specifically in the context of aging. Dr. Brown-Borg will present data on nutritional and genetic modulation of metabolism and how pathways converge to influence chromatin and epigenetic regulation of gene expression. Together our speakers explore new concepts in metabolism research that are of particular relevance to aging. This session aligns with the concept of GeroScience, the more we know of aging biology the better we understand diseases and disorders of aging. This session will demonstrate that metabolism, its regulation, and its influence on key processes linked to health and longevity, place it in a central position as we seek to discover targets and interventions to improve human aging.

The Rise and the Death of Senescent Cells: From Mechanisms to Interventions

Aging is at the root of age-related diseases and therapies targeting basic age-associated mechanisms have the potential to extend healthy lifespan. A common feature of older organisms is the accumulation of senescent cells – cells that have irreversibly lost the capacity to undergo replication. Senescent cells are characterized by an irreversible cell cycle arrest and by the Senescence-Associated Secretory Phenotype (SASP), which include many tissue remodeling and pro-inflammatory factors. Senescent cells are intermittently present during embryogenesis and in young organisms. On the contrary senescent cells accumulate and persist in aging tissues. Significantly, these persistent senescent cells can drive low-grade chronic inflammation, and their genetic or pharmacological elimination is sufficient to delay a number of diseases and to improve health span. Here, I will discuss the mechanisms by which senescent cells can promote tissue aging and dysfunction and the potential of targeting senescent cells to delay human aging.

A kognitív idegtudomány elmúlt 30 éve

A kognitív idegtudomány klasszikus területei közül a szerző összefoglalja az észlelés, figyelem, tanulás és emlékezés területének hazai idegtudományi vizsgálatait, főként az agyi elektromos működések módszerére koncentrálva. Külön területként mutatja be az öregedéssel kapcsolatos eredményeket.Concentrating on electrophysiological studies the author reviews Hungarian neuroscience research on the fields of perception, attention, learning and memory. As a specific topic, he reviews results on human aging.

The Evolution of the Hallmarks of Aging

The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the “hallmarks of aging,” i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging – the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called “layers of aging.” A difference should be made between the first four layers of unicellular aging, present in some unicellular organisms and in all multicellular opisthokonts, that stem and strike “from the inside” of individual cells and span from increasingly abnormal protein folding to deregulated nutrient sensing, and the last four layers of metacellular aging, progressively appearing in metazoans, that strike the cells of a multicellular organism “from the outside,” i.e., because of other cells, and span from transcriptional alterations to the disruption of intercellular communication. The evolution of metazoans and eumetazoans probably solved the problem of aging along with the problem of unicellular aging. However, metacellular aging originates in the mechanisms by which the effects of unicellular aging are kept under control – e.g., the exhaustion of stem cells that contribute to replace damaged somatic cells. In bilaterians, additional functions have taken a toll on generally useless potentially limited lifespan to increase the fitness of organisms at the price of a progressively less efficient containment of the damage of unicellular aging. In the end, this picture suggests that geroscience should be more efficient in targeting conditions of metacellular aging rather than unicellular aging itself.

Fission and PINK-1-mediated mitophagy are required for Insulin/IGF-1 signaling mutant reproductive longevity

Women′s reproductive cessation is the earliest sign of human aging and is caused by decreasing oocyte quality. Similarly, C. elegans′ reproduction declines with age and is caused by oocyte quality decline. Aberrant mitochondrial dynamics are a hallmark of age-related dysfunction, but the role of mitochondrial morphology in reproductive aging is largely unknown. We examined the requirements for mitochondrial fusion and fission in oocytes of both wild-type worms and the long-lived, long-reproducing insulin-like receptor mutant daf-2. We find that normal reproduction requires both fusion and fission. By contrast, daf-2 mutants require fission, but not fusion, for reproductive span extension. daf-2 mutant oocytes′ mitochondria are punctate (fissioned) and may be primed for mitophagy, as loss of the mitophagy regulator PINK-1 shortens daf-2′s reproductive span. Our data suggest that daf-2 maintain oocyte mitochondria quality with age via a shift toward punctate mitochondrial morphology and mitophagy to extend reproductive longevity.

Tyrosine Inhibits TyrRS-mediated DNA Repair and Induces Neuronal Oxidative DNA Damage

Human aging and neurodegenerative diseases accumulate oxidative DNA damage-associated mutations in neurons. Circadian-regulated tyrosine (Tyr) is increased during aging and in Alzheimer’s Disease (AD). Tyr exacerbates the cognitive decline in the elderly and AD patients. Tyrosyl-tRNA synthetase (TyrRS) that activates Tyr for protein synthesis and participates in DNA repair is depleted in the affected brain regions of AD patients through an unknown mechanism. Here, we found that increased Tyr levels decrease the nuclear and neurite levels of TyrRS in neurons and cause oxidative DNA damage. Although Tyr inhibits protein synthesis at the elongation step, dopamine (DA)- a neurotransmitter derived from Tyr increases TyrRS levels. We previously showed that Tyr inhibits TyrRS-mediated activation of poly-ADP-ribose polymerase 1 (PARP1), a modulator of DNA repair. We now found that trans-resveratrol (trans-RSV) that binds to TyrRS mimicking ‘Tyr conformation’ decreases TyrRS, inhibits DNA repair and induces neurotoxicity. Conversely, cis-RSV binds to TyrRS mimicking a ‘Tyr-free conformation,’ increases TyrRS, facilitates DNA repair, and protects neurons against multiple neurotoxic agents in a TyrRS-dependent manner. Our results suggest that increased Tyr levels may have causal effects in human aging and neurocognitive disorders and offer a plausible explanation to divergent results obtained in clinical trials using RSV.