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Review
. 2024 Aug;46(4):3711-3721.
doi: 10.1007/s11357-024-01101-7. Epub 2024 Feb 24.

Metabolic dysfunction and the development of physical frailty: an aging war of attrition

William A Fountain  1 , Taylor S Bopp  1 , Michael Bene  1 , Jeremy D Walston  2
Affiliations
Review

Metabolic dysfunction and the development of physical frailty: an aging war of attrition

William A Fountain et al. Geroscience. 2024 Aug.

Abstract

The World Health Organization recently declared 2021-2030 the decade of healthy aging. Such emphasis on healthy aging requires an understanding of the biologic challenges aging populations face. Physical frailty is a syndrome of vulnerability that puts a subset of older adults at high risk for adverse health outcomes including functional and cognitive decline, falls, hospitalization, and mortality. The physiology driving physical frailty is complex with age-related biological changes, dysregulated stress response systems, chronic inflammatory pathway activation, and altered energy metabolism all likely contributing. Indeed, a series of recent studies suggests circulating metabolomic distinctions can be made between frail and non-frail older adults. For example, marked restrictions on glycolytic and mitochondrial energy production have been independently observed in frail older adults and collectively appear to yield a reliance on the highly fatigable ATP-phosphocreatine (PCr) energy system. Further, there is evidence that age-associated impairments in the primary ATP generating systems (glycolysis, TCA cycle, electron transport) yield cumulative deficits and fail to adequately support the ATP-PCr system. This in turn may acutely contribute to several major components of the physical frailty phenotype including muscular fatigue, weakness, slow walking speed and, over time, result in low physical activity and accelerate reductions in lean body mass. This review describes specific age-associated metabolic declines and how they can collectively lead to metabolic inflexibility, ATP-PCr reliance, and the development of physical frailty. Further investigation remains necessary to understand the etiology of age-associated metabolic deficits and develop _targeted preventive strategies that maintain robust metabolic health in older adults.

Keywords: Aging; Energy; Frailty; Metabolism; Skeletal muscle.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Conceptual framework of triggers and physiological changes that influence physical frailty and adverse health outcomes. The etiology of physical frailty is thought to be multifactorial with dynamic, systemic physiological responses to various triggers resulting in the clinical presentation of physical frailty. Altered energy metabolism likely plays a central role in the development of physical frailty due to its robust influence on the physical function of skeletal muscle tissue. Specific age- and frailty-associated metabolic impairments have been independently observed and likely accumulate in a subset of individuals. Therefore, the cumulative attrition of multiple metabolic systems may yield a functional threshold indicating the development of physical frailty
Fig. 2
Fig. 2
Introduction to major bioenergetic systems in human skeletal muscle. To be utilized for energy production, circulating glucose and lipids must first be transported into the active cell where they can either be stored or enter their respective oxidative pathways. Glycolysis is responsible for the conversion of glucose to pyruvate, an important metabolic intermediate. Pyruvate dehydrogenase (PDH) then catalyzes the transformation of pyruvate into acetyl-CoA in the mitochondria. Similarly, intracellular fatty acids are shuttled into the mitochondria to generate acetyl-CoA through β-oxidation. Acetyl-CoA is one of the most essential metabolic intermediates as it is the primary substrate of the tricarboxylic acid cycle (TCA). In conjunction with the electron transport chain, most cellular energy is produced by the mitochondria in the form of adenosine triphosphate (ATP). Therefore, mitochondrial ATP generation is essential for the optimal function of the ATP-phosphocreatine (PCr) system. Importantly, ATP-PCr acts as an emergency energy reserve with the rapid interconversion of PCr + ADP to creatine (Cr) + ATP fueling brief periods of elevated metabolic demands
Fig. 3
Fig. 3
Hypothesized limitations of bioenergetic systems in physical frailty. Frail older adults are often characterized by marked muscle weakness and chronic fatigue. These symptoms could potentially be explained by a combination of known age-associated metabolic alterations. First, non-diabetic frail individuals have been reported to have transient glucose intolerance, suggestive of impaired skeletal muscle glucose uptake [16]. Second, frail individuals appear to have impaired CPT1-mediated fatty acid transport into the mitochondria [–29]. In addition, protein expression of mitochondrial energy systems including β-oxidation, TCA cycle, and the electron transport chain have all been shown to be downregulated with age [, , –56]. It is plausible that these impairments could reach a cumulative metabolic deficit reaching a threshold in certain individuals where the highly fatigable substrate-level phosphorylation systems (anaerobic glycolysis, ATP-PCr) become exhausted, resulting in the hallmark muscle weakness and fatigue identified in physically frail populations
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References

    1. Fried L, et al. Frailty in older adults: evidence for a phenotype. J Gerontol. 2001;56:M146–M157. doi: 10.1093/gerona/56.3.M146. - DOI - PubMed
    1. Fried L, et al. The physical frailty syndrome as a transition from homeostatic symphony to cacophony. Nat Aging. 2021;1:36–46. doi: 10.1038/s43587-020-00017-z. - DOI - PMC - PubMed
    1. Alvarez-Rodriguez L, et al. Aging is associated with circulating cytokine dysregulation. Cell Immunol. 2012;273(2):124–132. doi: 10.1016/j.cellimm.2012.01.001. - DOI - PubMed
    1. Ferrucci L, et al. The origins of age-related proinflammatory state. Blood. 2005;105(6):2294–2299. doi: 10.1182/blood-2004-07-2599. - DOI - PMC - PubMed
    1. Furman D, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25:1822–1832. doi: 10.1038/s41591-019-0675-0. - DOI - PMC - PubMed
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