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Nature Reviews. Drug Discovery Aug 2020Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in... (Review)
Review
Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.
Topics: Aging; Animals; Drug Discovery; Humans
PubMed: 32467649
DOI: 10.1038/s41573-020-0067-7 -
Aging Cell Dec 2020The idea that senescent cells are causally involved in aging has gained strong support from findings that the removal of such cells alleviates many age-related diseases... (Review)
Review
The idea that senescent cells are causally involved in aging has gained strong support from findings that the removal of such cells alleviates many age-related diseases and extends the life span of mice. While efforts proceed to make therapeutic use of such discoveries, it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence, in order better to understand the biology that we might seek to alter. Cellular senescence is often regarded as an anti-cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. This is difficult to reconcile with the simple idea of an anti-cancer mechanism. Furthermore, other studies have shown that cellular senescence is involved in wound healing and tissue repair. Here, we bring these findings and ideas together and discuss the possibility that these functions might be the main reason for the evolution of cellular senescence. Furthermore, we discuss the idea that senescent cells might accumulate with age because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).
Topics: Aging; Animals; Biological Evolution; Carcinogenesis; Cellular Senescence; Humans; Longevity; Mice; Models, Biological; Neoplasms; Wound Healing
PubMed: 33166065
DOI: 10.1111/acel.13270 -
Lancet (London, England) May 2016Although populations around the world are rapidly ageing, evidence that increasing longevity is being accompanied by an extended period of good health is scarce. A...
Although populations around the world are rapidly ageing, evidence that increasing longevity is being accompanied by an extended period of good health is scarce. A coherent and focused public health response that spans multiple sectors and stakeholders is urgently needed. To guide this global response, WHO has released the first World report on ageing and health, reviewing current knowledge and gaps and providing a public health framework for action. The report is built around a redefinition of healthy ageing that centres on the notion of functional ability: the combination of the intrinsic capacity of the individual, relevant environmental characteristics, and the interactions between the individual and these characteristics. This Health Policy highlights key findings and recommendations from the report.
Topics: Aging; Global Health; Health Policy; Humans; Longevity; Public Health; World Health Organization
PubMed: 26520231
DOI: 10.1016/S0140-6736(15)00516-4 -
The Lancet. Diabetes & Endocrinology Aug 2018During ageing, the secretory patterns of the hormones produced by the hypothalamic-pituitary axis change, as does the sensitivity of the axis to negative feedback by end... (Review)
Review
During ageing, the secretory patterns of the hormones produced by the hypothalamic-pituitary axis change, as does the sensitivity of the axis to negative feedback by end hormones. Additionally, glucose homoeostasis tends towards disequilibrium with increasing age. Along with these endocrine alterations, a loss of bone and muscle mass and strength occurs, coupled with an increase in fat mass. In addition, ageing-induced effects are difficult to disentangle from the influence of other factors that are common in older people, such as chronic diseases, inflammation, and low nutritional status, all of which can also affect endocrine systems. Traditionally, the decrease in hormone activity during the ageing process has been considered to be detrimental because of the related decline in bodily functions. The concept of hormone replacement therapy was suggested as a therapeutic intervention to stop or reverse this decline. However, clearly some of these changes are a beneficial adaptation to ageing, whereas hormonal intervention often causes important adverse effects. In this paper, we discuss the effects of age on the different hypothalamic-pituitary-hormonal organ axes, as well as age-related changes in calcium and bone metabolism and glucose homoeostasis.
Topics: Aging; Endocrine System; Hormones; Humans
PubMed: 30017799
DOI: 10.1016/S2213-8587(18)30026-3 -
Sub-cellular Biochemistry 2019With an increasingly ageing population that is expected to double by 2050 in the U.S., it is paramount that we further understand the neurological changes that occur... (Review)
Review
With an increasingly ageing population that is expected to double by 2050 in the U.S., it is paramount that we further understand the neurological changes that occur during ageing. This is relevant not only in the context of "pathological" ageing, where the development of many neurodegenerative disorders is typically a feature of only the older population (and indeed, age is the primary risk factor for many conditions such as Alzheimer's disease), but also for what is considered to be "normal" or "healthy" ageing. Specifically, a significant proportion of the older population are affected by "age-related cognitive decline" (ARCD), which is both independent of dementia and has an incidence 70% higher than dementia alone. However, whilst it is reported that there are pathogenic and phenotypic overlaps between healthy and pathological ageing, it is clear that there is a need to identify the pathways and understand the mechanisms that contribute to this loss of cognitive function with normal ageing, particularly in light of the increasing life expectancy of the global population. Importantly, there is an increasing body of evidence implicating zinc homeostasis as a key player in learning and memory and also potentially ARCD. Further research will ultimately contribute to the development of targeted therapeutics that will promote successful brain ageing. In this chapter we will explore the notion of ARCD, with a perspective on potential key neurochemical pathways that can be targeted for future intervention.
Topics: Aging; Alzheimer Disease; Cognition; Cognition Disorders; Humans; Zinc
PubMed: 30888651
DOI: 10.1007/978-981-13-3681-2_5 -
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 -
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 -
Sub-cellular Biochemistry 2018Understanding how the human gut microbiota might influence ageing is challenging. The gut microbiota is a hugely complex ecology of organisms that varies greatly with... (Review)
Review
Understanding how the human gut microbiota might influence ageing is challenging. The gut microbiota is a hugely complex ecology of organisms that varies greatly with individuals and time, making age-related changes difficult to measure. However, elderly and younger populations do show differences in gut microbe composition. The key question is whether these differences only reflect age-related changes in host physiology and diet, or if microbes can drive host ageing? Model organisms allow this question to be addressed. Longitudinal analyses in the fruit fly Drosophila melanogaster show that changes in microbial composition precedes intestinal and host ageing, and antibiotic treatment increases lifespan, implicating microbes in accelerating ageing. Antibiotics also extend the lifespan of middle-aged killifish but additional transplantation of gut microbes from young killifish extends lifespan further, suggesting a positive effect of microbes associated with young animals. Microbes from old, but not young, mice induce inflammation when added to germ-free mice suggesting that microbes become more harmful to the host with age. These studies implicate broad classes of bacteria, particularly members of the phylum Proteobacteria, as drivers of ageing in a feed-forward loop with intestinal degradation and inflammation. The nematode Caenorhabditis elegans can be associated with single strains of genetically-tractable bacteria, and this simplified system has revealed specific interventions in bacterial metabolism, such as inhibition of bacterial folate synthesis, that extend animal lifespan. Transferring this understanding to the human microbiota is challenging but promises to reveal how manipulation of the gut microbiota might be a route to maintain health in old age.
Topics: Aging; Animals; Anti-Bacterial Agents; Drosophila melanogaster; Gastrointestinal Microbiome; Humans; Inflammation; Intestines; Longevity
PubMed: 30779015
DOI: 10.1007/978-981-13-2835-0_12 -
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