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Nature Reviews. Drug Discovery Oct 2017Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might... (Review)
Review
Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.
Topics: Aging; Animals; Atherosclerosis; Cell Cycle Checkpoints; Cell Proliferation; Cellular Senescence; Humans; Neoplasms
PubMed: 28729727
DOI: 10.1038/nrd.2017.116 -
Cell Mar 2015Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Recent... (Review)
Review
Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles. Nutritional modulation of the microbiome can also be important, and there are long-term, including inter-generational, effects of diet. The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during aging to diet and genetic variation in the response to diet are being identified. These new findings are opening the way to specific dietary and pharmacological interventions to recapture the full potential benefits of dietary restriction, which humans can find difficult to maintain voluntarily.
Topics: Aging; Animals; Caloric Restriction; Diet; Health Promotion; Humans; Longevity; Models, Animal
PubMed: 25815989
DOI: 10.1016/j.cell.2015.02.020 -
Ageing Research Reviews Jul 2023Epigenetic aging clocks have gained significant attention as a tool for predicting age-related health conditions in clinical and research settings. They have enabled... (Review)
Review
Epigenetic aging clocks have gained significant attention as a tool for predicting age-related health conditions in clinical and research settings. They have enabled geroscientists to study the underlying mechanisms of aging and assess the effectiveness of anti-aging therapies, including diet, exercise and environmental exposures. This review explores the effects of modifiable lifestyle factors' on the global DNA methylation landscape, as seen by aging clocks. We also discuss the underlying mechanisms through which these factors contribute to biological aging and provide comments on what these findings mean for people willing to build an evidence-based pro-longevity lifestyle.
Topics: Humans; Epigenesis, Genetic; Aging; Longevity; DNA Methylation; Diet
PubMed: 37211319
DOI: 10.1016/j.arr.2023.101956 -
Nutrients Jun 2016Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age sample there is a considerable variation in the extent of... (Review)
Review
Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age sample there is a considerable variation in the extent of disease and functional impairment risk, revealing a need for valid biomarkers to aid in characterizing the complex aging processes. The identification of biomarkers is further complicated by the diversity of biological living situations, lifestyle activities and medical treatments. Thus, there has been no identification of a single biomarker or gold standard tool that can monitor successful or healthy aging. Within this short review the current knowledge of putative biomarkers is presented, focusing on their application to the major physiological mechanisms affected by the aging process including physical capability, nutritional status, body composition, endocrine and immune function. This review emphasizes molecular and DNA-based biomarkers, as well as recent advances in other biomarkers such as microRNAs, bilirubin or advanced glycation end products.
Topics: Aging; Bilirubin; Biomarkers; DNA; Glycation End Products, Advanced; Humans; MicroRNAs
PubMed: 27271660
DOI: 10.3390/nu8060338 -
Epidemiology and Psychiatric Sciences Dec 2017The extension of life does not appear to be slowing, representing a great achievement for mankind as well as a challenge for ageing populations. As we move towards an...
The extension of life does not appear to be slowing, representing a great achievement for mankind as well as a challenge for ageing populations. As we move towards an increasingly older population we will need to find novel ways for individuals to make the best of the challenges they face, as the likelihood of encountering some form of adversity increases with age. Resilience theories share a common idea that individuals who manage to navigate adversity and maintain high levels of functioning demonstrate resilience. Traditional models of healthy ageing suggest that having a high level of functioning across a number of domains is a requirement. The addition of adversity to the healthy ageing model via resilience makes this concept much more accessible and more amenable to the ageing population. Through asset-based approaches, such as the invoking of individual, social and environmental resources, it is hoped that greater resilience can be fostered at a population level. Interventions aimed at fostering greater resilience may take many forms; however, there is great potential to increase social and environmental resources through public policy interventions. The wellbeing of the individual must be the focus of these efforts; quality of life is an integral component to the enjoyment of additional years and should not be overlooked. Therefore, it will become increasingly important to use resilience as a public health concept and to intervene through policy to foster greater resilience by increasing resources available to older people. Fostering wellbeing in the face of increasing adversity has significant implications for ageing individuals and society as a whole.
Topics: Adaptation, Psychological; Aged; Aging; Health Status; Healthy Aging; Humans; Male; Mental Health; Quality of Life; Resilience, Psychological; Social Support
PubMed: 28679453
DOI: 10.1017/S2045796017000324 -
Nature Oct 2021Time-restricted feeding (TRF) has recently gained interest as a potential anti-ageing treatment for organisms from Drosophila to humans. TRF restricts food intake to...
Time-restricted feeding (TRF) has recently gained interest as a potential anti-ageing treatment for organisms from Drosophila to humans. TRF restricts food intake to specific hours of the day. Because TRF controls the timing of feeding, rather than nutrient or caloric content, TRF has been hypothesized to depend on circadian-regulated functions; the underlying molecular mechanisms of its effects remain unclear. Here, to exploit the genetic tools and well-characterized ageing markers of Drosophila, we developed an intermittent TRF (iTRF) dietary regimen that robustly extended fly lifespan and delayed the onset of ageing markers in the muscles and gut. We found that iTRF enhanced circadian-regulated transcription and that iTRF-mediated lifespan extension required both circadian regulation and autophagy, a conserved longevity pathway. Night-specific induction of autophagy was both necessary and sufficient to extend lifespan on an ad libitum diet and also prevented further iTRF-mediated lifespan extension. By contrast, day-specific induction of autophagy did not extend lifespan. Thus, these results identify circadian-regulated autophagy as a critical contributor to iTRF-mediated health benefits in Drosophila. Because both circadian regulation and autophagy are highly conserved processes in human ageing, this work highlights the possibility that behavioural or pharmaceutical interventions that stimulate circadian-regulated autophagy might provide people with similar health benefits, such as delayed ageing and lifespan extension.
Topics: Aging; Animals; Autophagy; Biomarkers; Circadian Clocks; Circadian Rhythm; Darkness; Drosophila melanogaster; Feeding Behavior; Female; Longevity; Male; Time Factors
PubMed: 34588695
DOI: 10.1038/s41586-021-03934-0 -
Nature Reviews. Genetics Feb 2020The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an... (Review)
Review
The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an understanding of the underlying mechanisms of ageing, and genetics is a powerful tool for identifying these mechanisms. Large-scale genome-wide association studies have recently identified many loci that influence key human ageing traits, including lifespan. Multi-trait loci have been linked with several age-related diseases, suggesting shared ageing influences. Mutations that drive accelerated ageing in prototypical progeria syndromes in humans point to an important role for genome maintenance and stability. Together, these different strands of genetic research are highlighting pathways for the discovery of anti-ageing interventions that may be applicable in humans.
Topics: Aging; Animals; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Longevity; Mutation; Phenotype; Reproduction
PubMed: 31690828
DOI: 10.1038/s41576-019-0183-6 -
Nature Communications Mar 2023Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely on glycolysis for energy...
Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely on glycolysis for energy production, little is known about the role of glycolysis in ECs senescence. Here, we report a critical role for glycolysis-derived serine biosynthesis in preventing ECs senescence. During senescence, the expression of serine biosynthetic enzyme PHGDH is significantly reduced due to decreased transcription of the activating transcription factor ATF4, which leads to reduction of intracellular serine. PHGDH prevents premature senescence primarily by enhancing the stability and activity of pyruvate kinase M2 (PKM2). Mechanistically, PHGDH interacts with PKM2, which prevents PCAF-catalyzed PKM2 K305 acetylation and subsequent degradation by autophagy. In addition, PHGDH facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and stimulates its activity to phosphorylate H3T11 and regulate the transcription of senescence-associated genes. Vascular endothelium-targeted expression of PHGDH and PKM2 ameliorates ageing in mice. Our findings reveal that enhancing serine biosynthesis could become a therapy to promote healthy ageing.
Topics: Animals; Mice; Cellular Senescence; Endothelial Cells; Glycolysis; Histones; Phosphoglycerate Dehydrogenase; Pyruvate Kinase; Serine; Aging
PubMed: 36899022
DOI: 10.1038/s41467-023-37094-8 -
Cellular and Molecular Life Sciences :... Jun 2023Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline of the organism's fitness. In the brain, ageing is highly... (Review)
Review
Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline of the organism's fitness. In the brain, ageing is highly associated with cognitive decline and neurodegenerative diseases. With the rise in life expectancy, characterizing the brain ageing process becomes fundamental for developing therapeutic interventions against the increased incidence of age-related neurodegenerative diseases and to aim for an increase in human life span and, more importantly, health span. In this review, we start by introducing the molecular/cellular hallmarks associated with brain ageing and their impact on brain cell populations. Subsequently, we assess emerging evidence on how systemic ageing translates into brain ageing. Finally, we revisit the mainstream and the novel rejuvenating strategies, discussing the most successful ones in delaying brain ageing and related diseases.
Topics: Humans; Aging; Brain; Longevity; Neurodegenerative Diseases
PubMed: 37354261
DOI: 10.1007/s00018-023-04832-6 -
Diabetologia Oct 2019Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent... (Review)
Review
Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent cells in various tissues increases with age, obesity and diabetes. Senescent cells have been directly implicated in the generation of insulin resistance. Recently, drugs that preferentially target senescent cells, known as senolytics, have been described and recently entered clinical trials. In this review, we explore the biological links between ageing and diabetes, specifically focusing on cellular senescence. We summarise the current data on cellular senescence in key target tissues associated with the development and clinical phenotypes of type 2 diabetes and discuss the therapeutic potential of targeting cellular senescence in diabetes.
Topics: Aging; Animals; Cellular Senescence; Diabetes Mellitus, Type 2; Humans
PubMed: 31451866
DOI: 10.1007/s00125-019-4934-x