-
Cell Aug 2023With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field.... (Review)
Review
With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.
Topics: Humans; Longevity; Aging; Biomarkers
PubMed: 37657418
DOI: 10.1016/j.cell.2023.08.003 -
Ageing Research Reviews Jul 2023Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of... (Review)
Review
Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of aging, the role of mitochondrial quality control (MQC) in aging is still poorly understood. A growing body of evidence points out that reactive oxygen species (ROS) stimulates mitochondrial dynamic changes and accelerates the accumulation of oxidized by-products through mitochondrial proteases and mitochondrial unfolded protein response (UPR). Mitochondrial-derived vesicles (MDVs) are the frontline of MQC to dispose of oxidized derivatives. Besides, mitophagy helps remove partially damaged mitochondria to ensure that mitochondria are healthy and functional. Although abundant interventions on MQC have been explored, over-activation or inhibition of any type of MQC may even accelerate abnormal energy metabolism and mitochondrial dysfunction-induced senescence. This review summarizes mechanisms essential for maintaining mitochondrial homeostasis and emphasizes that imbalanced MQC may accelerate cellular senescence and aging. Thus, appropriate interventions on MQC may delay the aging process and extend lifespan.
Topics: Humans; Aging; Cellular Senescence; Mitochondria; Reactive Oxygen Species; Longevity
PubMed: 37196864
DOI: 10.1016/j.arr.2023.101955 -
Nature Aug 2023Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated...
Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.
Topics: Animals; Humans; Mice; Aging; Brain; Bystander Effect; Cognitive Dysfunction; DNA; Inflammation; Membrane Proteins; Memory Disorders; Microglia; Mitochondria; Neurodegenerative Diseases; Nucleotidyltransferases; Organ Specificity; Signal Transduction; Hippocampus
PubMed: 37532932
DOI: 10.1038/s41586-023-06373-1 -
The New England Journal of Medicine Oct 2023
Review
Topics: Humans; Aging; Cellular Senescence; Precancerous Conditions; Stem Cells
PubMed: 37792614
DOI: 10.1056/NEJMra2304431 -
Nature Metabolism Dec 2023Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully... (Review)
Review
Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities. Preclinical and clinical studies have shown that impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. Strategies to boost mitophagy have been successfully tested in model organisms, and, recently, some have been translated into clinics. In this Review, we describe the basic mechanisms of mitophagy and how mitophagy can be assessed in human blood, the immune system and tissues, including muscle, brain and liver. We outline mitophagy's role in specific diseases and describe mitophagy-activating approaches successfully tested in humans, including exercise and nutritional and pharmacological interventions. We describe how mitophagy is connected to other features of ageing through general mechanisms such as inflammation and oxidative stress and forecast how strengthening research on mitophagy and mitophagy interventions may strongly support human health.
Topics: Humans; Mitophagy; Aging; Mitochondria; Oxidative Stress
PubMed: 38036770
DOI: 10.1038/s42255-023-00930-8 -
Mechanisms of Ageing and Development Jul 2023The current understanding of the biology of aging is largely based on research aimed at identifying factors that influence lifespan. However, lifespan as a sole proxy... (Review)
Review
The current understanding of the biology of aging is largely based on research aimed at identifying factors that influence lifespan. However, lifespan as a sole proxy measure of aging has limitations because it can be influenced by specific pathologies (not generalized physiological deterioration in old age). Hence, there is a great need to discuss and design experimental approaches that are well-suited for studies targeting the biology of aging, rather than the biology of specific pathologies that restrict the lifespan of a given species. For this purpose, we here review various perspectives on aging, discuss agreement and disagreement among researchers on the definition of aging, and show that while slightly different aspects are emphasized, a widely accepted feature, shared across many definitions, is that aging is accompanied by phenotypic changes that occur in a population over the course of an average lifespan. We then discuss experimental approaches that are in line with these considerations, including multidimensional analytical frameworks as well as designs that facilitate the proper assessment of intervention effects on aging rate. The proposed framework can guide discovery approaches to aging mechanisms in all key model organisms (e.g., mouse, fish models, D. melanogaster, C. elegans) as well as in humans.
Topics: Animals; Humans; Mice; Aging; Caenorhabditis elegans; Drosophila melanogaster; Longevity
PubMed: 37302556
DOI: 10.1016/j.mad.2023.111837 -
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 -
Pharmacological Reviews Jul 2023An increase in life expectancy in developed countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided... (Review)
Review
An increase in life expectancy in developed countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided evidence of the prominent role of cellular senescence in many of these pathologies. Key traits of senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secretory phenotype resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senescence is a highly phenotypically heterogeneous process, hindering the discovery of totally specific and accurate biomarkers. Also, strategies to prevent the pathologic effect of senescent cell accumulation during aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies, and some are already in early stages of clinical translation. The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiologic functions. In this review, we explore the heterogeneous phenotype of senescent cells and its influence on the expression of biomarkers currently used for senescence detection. We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies. SIGNIFICANCE STATEMENT: This paper is an extensive review of what is currently known about the complex process of cellular senescence and explores its most defining features. The main body of the discussion focuses on how the multifeature fluctuation of the senescence phenotype and the physiological role of cellular senescence have both caused a limitation in the search for truly reliable senescence biomarkers and the progression in the development of senotherapies.
Topics: Humans; Reproducibility of Results; Senotherapeutics; Cellular Senescence; Aging; Biomarkers; Chronic Disease
PubMed: 36732079
DOI: 10.1124/pharmrev.122.000622 -
Neuroscience and Biobehavioral Reviews Jul 2024
Topics: Humans; Aging; Neurotransmitter Agents; Animals; Brain
PubMed: 38574783
DOI: 10.1016/j.neubiorev.2024.105647 -
Cold Spring Harbor Perspectives in... Jun 2024Aging can be conceptualized as the progressive disequilibrium between stochastic damage accumulation and resilience mechanisms that continuously repair that damage,... (Review)
Review
Aging can be conceptualized as the progressive disequilibrium between stochastic damage accumulation and resilience mechanisms that continuously repair that damage, which eventually cause the development of chronic disease, frailty, and death. The immune system is at the forefront of these resilience mechanisms. Indeed, aging is associated with persistent activation of the immune system, witnessed by a high circulating level of inflammatory markers and activation of immune cells in the circulation and in tissue, a condition called "inflammaging." Like aging, inflammaging is associated with increased risk of many age-related pathologies and disabilities, as well as frailty and death. Herein we discuss recent advances in the understanding of the mechanisms leading to inflammaging and the intrinsic dysregulation of the immune function that occurs with aging. We focus on the underlying mechanisms of chronic inflammation, in particular the role of NF-κB and recent studies targeting proinflammatory mediators. We further explore the dysregulation of the immune response with age and immunosenescence as an important mechanistic immune response to acute stressors. We examine the role of the gastrointestinal microbiome, age-related dysbiosis, and the integrated stress response in modulating the inflammatory "response" to damage accumulation and stress. We conclude by focusing on the seminal question of whether reducing inflammation is useful and the results of related clinical trials. In summary, we propose that inflammation may be viewed both as a clinical biomarker of the failure of resilience mechanisms and as a causal factor in the rising burden of disease and disabilities with aging. The fact that inflammation can be reduced through nonpharmacological interventions such as diet and exercise suggests that a life course approach based on education may be a successful strategy to increase the health span with few adverse consequences.
Topics: Humans; Inflammation; Aging; Gastrointestinal Microbiome; Immunosenescence; NF-kappa B; Animals; Dysbiosis
PubMed: 38052484
DOI: 10.1101/cshperspect.a041197