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      Measuring biological aging in humans: A quest

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          Abstract

          The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

          Abstract

          Finding a reference metric for the rate of biological aging is key to understanding the molecular nature of the aging process. Defining and validating this metric in humans opens the door to a new kind of medicine that will overcome the limitation of current disease definitions. We will then be able to approach health in a global perspective and bring life course preventative measures to the center of attention.

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          Most cited references211

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          An epigenetic biomarker of aging for lifespan and healthspan

          Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.
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            Cellular senescence in aging and age-related disease: from mechanisms to therapy.

            Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy.
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              Autophagy maintains stemness by preventing senescence.

              During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.
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                Author and article information

                Contributors
                FerrucciLu@grc.nia.nih.gov
                Journal
                Aging Cell
                Aging Cell
                10.1111/(ISSN)1474-9726
                ACEL
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                1474-9718
                1474-9726
                12 December 2019
                February 2020
                : 19
                : 2 ( doiID: 10.1111/acel.v19.2 )
                : e13080
                Affiliations
                [ 1 ] Translational Gerontology Branch Biomedical Research Center National Institute on Aging National Institutes of Health Baltimore MD USA
                [ 2 ] Department of Medical and Surgical Sciences University of Bologna Bologna Italy
                [ 3 ] Department of Epidemiology and Public Health University of Maryland School of Medicine Baltimore MD USA
                [ 4 ] Division of Aging Biology National Institute on Aging NIH Bethesda MD USA
                Author notes
                [*] [* ] Correspondence

                Luigi Ferrucci, Intramural Research Program, National Institute on Aging, 251 Bayview Boulevard, Baltimore, MD 21224, USA.

                Email: FerrucciLu@ 123456grc.nia.nih.gov

                Author information
                https://orcid.org/0000-0002-3354-2442
                Article
                ACEL13080
                10.1111/acel.13080
                6996955
                31833194
                f1414d6b-fdea-4c1f-bd7b-cc71e18391fb
                © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 July 2019
                : 22 October 2019
                : 27 October 2019
                Page count
                Figures: 3, Tables: 1, Pages: 21, Words: 19883
                Funding
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Funded by: National Institute on Aging , open-funder-registry 10.13039/100000049;
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                February 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:03.02.2020

                Cell biology
                aging,biological aging,hallmarks of aging,inflammation,multimorbidity,resilience,senescence
                Cell biology
                aging, biological aging, hallmarks of aging, inflammation, multimorbidity, resilience, senescence

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