Researchers: Laís R Perazza, Holly M Brown-Borg, LaDora V Thompson
Frailty is a complex syndrome affecting a growing sector of the global population as medical developments have advanced human mortality rates across the world. Our current understanding of frailty is derived from studies conducted in the laboratory as well as the clinic, which have generated largely phenotypic information. Far fewer studies have uncovered biological underpinnings driving the onset and progression of frailty, but the stage is set to advance the field with preclinical and clinical assessment tools, multiomics approaches together with physiological and biochemical methodologies. In this article, we provide comprehensive coverage of topics regarding frailty assessment, preclinical models, interventions, and challenges as well as clinical frameworks and prevalence. We also identify central biological mechanisms that may be at play including mitochondrial dysfunction, epigenetic alterations, and oxidative stress that in turn, affect metabolism, stress responses, and endocrine and neuromuscular systems. We review the role of metabolic syndrome, insulin resistance and visceral obesity, focusing on glucose homeostasis, adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and nicotinamide adenine dinucleotide (NAD+ ) as critical players influencing the age-related loss of health. We further focus on how immunometabolic dysfunction associates with oxidative stress in promoting sarcopenia, a key contributor to slowness, weakness, and fatigue. We explore the biological mechanisms involved in stem cell exhaustion that affect regeneration and may contribute to the frailty-associated decline in resilience and adaptation to stress. Together, an overview of the interplay of aging biology with genetic, lifestyle, and environmental factors that contribute to frailty, as well as potential therapeutic targets to lower risk and slow the progression of ongoing disease is covered. © 2022 American Physiological Society. Compr Physiol 12:1-46, 2022.
References
- Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies.
- A toolbox for the longitudinal assessment of healthspan in aging mice.
- Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds.
- Calorie Restriction and Aging in Humans.
- Novel individualized power training protocol preserves physical function in adult and older mice.
- Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner.
- Interventions to Slow Aging in Humans: Are We Ready?
- The hallmarks of aging.
- Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities.
- Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice.
- A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice.
- Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity.
- High intensity interval training improves physical performance in aged female mice: A comparison of mouse frailty assessment tools.
- The age-related loss of skeletal muscle mass and function: Measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans.
- Caloric restriction: implications for sarcopenia and potential mechanisms.