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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 -
Progress in Lipid Research Jul 2023Lipids play important roles in energy metabolism along with diverse aspects of biological membrane structure, signaling and other functions. Perturbations of lipid... (Review)
Review
Lipids play important roles in energy metabolism along with diverse aspects of biological membrane structure, signaling and other functions. Perturbations of lipid metabolism are responsible for the development of various pathologies comprising metabolic syndrome, obesity, and type 2 diabetes. Accumulating evidence suggests that circadian oscillators, operative in most cells of our body, coordinate temporal aspects of lipid homeostasis. In this review we summarize current knowledge on the circadian regulation of lipid digestion, absorption, transportation, biosynthesis, catabolism, and storage. Specifically, we focus on the molecular interactions between functional clockwork and biosynthetic pathways of major lipid classes comprising cholesterol, fatty acids, triacylglycerols, glycerophospholipids, glycosphingolipids, and sphingomyelins. A growing body of epidemiological studies associate a socially imposed circadian misalignment common in modern society with growing incidence of metabolic disorders, however the disruption of lipid metabolism rhythms in this connection has only been recently revealed. Here, we highlight recent studies that unravel the mechanistic link between intracellular molecular clocks, lipid homeostasis and development of metabolic diseases based on animal models of clock disruption and on innovative translational studies in humans. We also discuss the perspectives of manipulating circadian oscillators as a potentially powerful approach for preventing and managing metabolic disorders in human patients.
Topics: Animals; Humans; Lipid Metabolism; Circadian Rhythm; Circadian Clocks; Diabetes Mellitus, Type 2; Energy Metabolism; Metabolic Diseases; Lipids
PubMed: 37187314
DOI: 10.1016/j.plipres.2023.101235 -
Annual Review of Biomedical Engineering Jun 2023The process of aging manifests from a highly interconnected network of biological cascades resulting in the degradation and breakdown of every living organism over time.... (Review)
Review
The process of aging manifests from a highly interconnected network of biological cascades resulting in the degradation and breakdown of every living organism over time. This natural development increases risk for numerous diseases and can be debilitating. Academic and industrial investigators have long sought to impede, or potentially reverse, aging in the hopes of alleviating clinical burden, restoring functionality, and promoting longevity. Despite widespread investigation, identifying impactful therapeutics has been hindered by narrow experimental validation and the lack of rigorous study design. In this review, we explore the current understanding of the biological mechanisms of aging and how this understanding both informs and limits interpreting data from experimental models based on these mechanisms. We also discuss select therapeutic strategies that have yielded promising data in these model systems with potential clinical translation. Lastly, we propose a unifying approach needed to rigorously vet current and future therapeutics and guide evaluation toward efficacious therapies.
Topics: Humans; Aging; Longevity; Models, Biological; Models, Theoretical; Rejuvenation
PubMed: 37289554
DOI: 10.1146/annurev-bioeng-120122-123054 -
Nature Medicine Feb 2024The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict... (Review)
Review
The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.
Topics: Longevity; Biomarkers; Consensus; Research Design
PubMed: 38355974
DOI: 10.1038/s41591-023-02784-9 -
Science Advances Jun 2023Quantifying aging rate is important for evaluating age-associated decline and mortality. A blood single-cell RNA sequencing dataset for seven supercentenarians (SCs) was...
Quantifying aging rate is important for evaluating age-associated decline and mortality. A blood single-cell RNA sequencing dataset for seven supercentenarians (SCs) was recently generated. Here, we generate a reference 28-sample aging cohort to compute a single-cell level aging clock and to determine the biological age of SCs. Our clock model placed the SCs at a blood biological age to between 80.43 and 102.67 years. Compared to the model-expected aging trajectory, SCs display increased naive CD8 T cells, decreased cytotoxic CD8 T cells, memory CD4 T cells, and megakaryocytes. As the most prominent molecular hallmarks at the single-cell level, SCs contain more cells and cell types with high ribosome level, which is associated with and, according to Bayesian network inference, contributes to a low inflammation state and slow aging of SCs. Inhibiting ribosomal activity or translation in monocytes validates such translation against inflammation balance revealed by our single-cell aging clock.
Topics: Humans; Aged, 80 and over; Longevity; CD8-Positive T-Lymphocytes; Leukocytes, Mononuclear; Bayes Theorem; Single-Cell Gene Expression Analysis; Aging; Cellular Senescence; Inflammation; Ribosomes
PubMed: 37379396
DOI: 10.1126/sciadv.abq7599 -
Annual Review of Neuroscience Jul 2023This review explores the interface between circadian timekeeping and the regulation of brain function by astrocytes. Although astrocytes regulate neuronal activity... (Review)
Review
This review explores the interface between circadian timekeeping and the regulation of brain function by astrocytes. Although astrocytes regulate neuronal activity across many time domains, their cell-autonomous circadian clocks exert a particular role in controlling longer-term oscillations of brain function: the maintenance of sleep states and the circadian ordering of sleep and wakefulness. This is most evident in the central circadian pacemaker, the suprachiasmatic nucleus, where the molecular clock of astrocytes suffices to drive daily cycles of neuronal activity and behavior. In Alzheimer's disease, sleep impairments accompany cognitive decline. In mouse models of the disease, circadian disturbances accelerate astroglial activation and other brain pathologies, suggesting that daily functions in astrocytes protect neuronal homeostasis. In brain cancer, treatment in the morning has been associated with prolonged survival, and gliomas have daily rhythms in gene expression and drug sensitivity. Thus, circadian time is fast becoming critical to elucidating reciprocal astrocytic-neuronal interactions in health and disease.
Topics: Mice; Animals; Astrocytes; Circadian Rhythm; Circadian Clocks; Sleep; Suprachiasmatic Nucleus
PubMed: 36854316
DOI: 10.1146/annurev-neuro-100322-112249 -
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 -
Genome Research Aug 2023Accurately measuring biological age is crucial for improving healthcare for the elderly population. However, the complexity of aging biology poses challenges in how to...
Accurately measuring biological age is crucial for improving healthcare for the elderly population. However, the complexity of aging biology poses challenges in how to robustly estimate aging and interpret the biological significance of the traits used for estimation. Here we present SCALE, a statistical pipeline that quantifies biological aging in different tissues using explainable features learned from literature and single-cell transcriptomic data. Applying SCALE to the "Mouse Aging Cell Atlas" () data, we identified tissue-level transcriptomic aging programs for more than 20 murine tissues and created a multitissue resource of mouse quantitative aging-associated genes. We observe that SCALE correlates well with other age indicators, such as the accumulation of somatic mutations, and can distinguish subtle differences in aging even in cells of the same chronological age. We further compared SCALE with other transcriptomic and methylation "clocks" in data from aging muscle stem cells, Alzheimer's disease, and heterochronic parabiosis. Our results confirm that SCALE is more generalizable and reliable in assessing biological aging in aging-related diseases and rejuvenating interventions. Overall, SCALE represents a valuable advancement in our ability to measure aging accurately, robustly, and interpretably in single cells.
Topics: Animals; Mice; Aging; Gene Expression Profiling; Phenotype; Transcriptome; Models, Biological
PubMed: 37524436
DOI: 10.1101/gr.277491.122