Autophagy and metabolic aging: Current understanding and future applications

Abstract “Metabolic aging” refers to the gradual decline in cellular metabolic function across various tissues due to defective hormonal signaling, impaired nutrient sensing, mitochondrial dysfunction, replicative stress, and cellular senescence. While this process usually corresponds with chronological aging, the recent increase in metabolic diseases and cancers occurring at younger ages in humans suggests the premature onset of cellular fatigue and metabolic aging. Autophagy, a cellular housekeeping process facilitated by lysosomes, plays a crucial role in maintaining tissue rejuvenation and health. However, various environmental toxins, hormones, lifestyle changes, and nutrient imbalances can disrupt autophagy in humans. In this review, we explore the connection between autophagy and cellular metabolism, its regulation by extrinsic factors and its modulation to prevent the early onset of metabolic aging.

Sadly behind a paywall here is the intro:

Aging is a complex and inevitable process affecting all living beings. Metabolic aging, a fundamental aspect of aging, entails a progressive decline in cellular and physiological functions as individuals age. It is manifested by changes in hormone levels, disrupted nutrient-sensing, genomic instability, telomere attrition, epigenetic modifications, mitochondrial dysfunction, proteostasis defects, cellular senescence, altered intercellular communication, and a gradual decline in metabolic rate [1]. These age-related metabolic changes and molecular exhaustion pose significant risks for major human diseases, including diabetes, cardiovascular disorders, neurodegenerative diseases, and cancer. While these age-related changes in metabolism typically occur gradually over time, the dramatic rise in metabolic diseases and cancers among younger individuals suggests there is hastened onset of cellular fatigue and metabolic aging. Metabolic insults, such as chronic inflammation, oxidative stress, and insulin resistance, resulting from factors like poor diet, sedentary lifestyle, environmental toxins, all contribute to accelerate the aging process by damaging cells and tissues, and ultimately lead to premature aging.

The modern lifestyle involves over-exposure to processed foods, nutrient imbalance, and contact with environmental toxins, that place a significant metabolic burden on cells. This leads to oxidative stress, endoplasmic reticulum (ER) stress and inflammation, that when combined with impaired cellular repair mechanisms, ultimately cause premature cellular fatigue and metabolic exhaustion. Metabolic syndrome (MetS) disrupts the metabolic balance of several organs, including the liver, heart, pancreas, and adipose tissue [2]. Evidence from numerous studies indicates that obesity accelerates aging, as the metabolic dysregulation associated with obesity is strikingly similar to that observed in normal aging. The adipose tissues of obese subjects exhibit mitochondrial dysfunction, cellular senescence, and chronic inflammation, that mirror changes found in aging. Furthermore, obese and elderly individuals share similar adipose tissue immunological profiles [3]. The molecular and cellular mechanisms common to both obesity and aging have systemic consequences that predispose the individuals to similar chronic health complications [4]. For example, in obesity, excessive utilization of fat progenitor cells (pre-adipocytes) causes them to lose their specialized characteristics and acquire a senescent phenotype, that impair adipogenesis and their ability to sequester lipotoxic fatty acids, and induce the production of inflammatory cytokines and chemokines. Excessive calorie intake and exposure to environmental stressors, potentially can overwhelm the autophagic machinery, compromising cellular risilience early in life. Consequently, cellular fatigue commences sooner than expected to, promoting the premature onset of metabolic diseases in younger individuals. Additionally, disruptions in circadian rhythms, prevalent in contemporary living, can affect metabolic processes and exacerbate cellular aging [5]. Therefore, it is crucial to identify therapeutic interventions that promote ‘healthy aging’ and curtail age-related pathological conditions.

Macroautophagy (hereafter referred to as autophagy), is a highly conserved pathway of lysosomal degradation essential for cellular homeostasis, quality control, and adaption to stress. It facilitates nutrient recycling and maintains cellular homeostasis by selectively engulfing and degrading damaged or superfluous organelles, misfolded or long-lived proteins, and other cellular debris to generate energy. Autophagy also acts as a dynamic response to various stressors such as nutrient deprivation, infection, and oxidative stress. However, as cells age, the efficiency of autophagy declines, leading to the accumulation of cellular damage and build-up of cellular waste, which impairs cell function and results in metabolic derangement over time [6]. The expression of autophagy-related genes (ATGs), such as ATG5, ATG7 and BECN1, decreases with age in humans [7]. The regulatory interplay between autophagy and cellular metabolism is critical for normal development, physiological integrity, and disease prevention. Normal levels and regulation of autophagy are recognized as key biological processes that promote health and longevity [8]. Recently, compromised autophagy has been identified as one of the new hallmarks of aging [9]. Understanding the intricate relationship between autophagy and metabolic aging is important for uncovering strategies to promote healthy aging and potentially extend lifespan. This review provides insights into the key mechanisms in which autophagy dysregulation contributes to the premature aging of cells and the development of metabolic disorders.


this 23 page review article with 287 references maybe worthwhile.

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