Does eating less make you live longer and better? An update on calorie restriction

Abstract

The complexity of aging is hard to be captured. However, apart from its tissue-specific features, a structural and functional progressive decline of the whole organism that leads to death, often preceded by a phase of chronic morbidity, characterizes the common process of aging. Therefore, the research goal of scientists in the field moved from the search for strategies able to extend longevity to those ensuring healthy aging associated with a longer lifespan referred to as "healthspan". The aging process is plastic and can be tuned by multiple mechanisms including dietary and genetic interventions. To date, the most robust approach, efficient in warding off the cellular markers of aging, is calorie restriction (CR). Here, after a preliminary presentation of the major debate originated by CR, we concisely overviewed the recent results of CR treatment on humans. We also provided an update on the molecular mechanisms involved by CR and the effects on some of the age-associated cellular markers. We finally reviewed a number of tested CR mimetics and concluded with an evaluation of future applications of such dietary approach.

Keywords: CR mimetics; CR molecular mechanisms; aging; calorie restriction; studies on humans.

Figure 1

Calorie restriction (CR) impacts various cellular pathways and induces responses of the whole organism, leading to a more efficient metabolism, a higher protection against cellular damage, and the activation of remodeling mechanisms, whereas less efficient metabolism and synthetic pathways are blocked. CR inhibits processes involved in cell proliferation and glycolysis by blocking IGF-1 receptor-dependent pathways and TOR-dependent activities. CR exerts an anti-inflammatory effect by inhibiting nuclear factor-kB (NF-kB) activity. CR also decreases the production of ROS and increases mitochondrial biogenesis through different pathways (AMPK, sirtuins, and eNOS) leading to an improved mitochondrial physiology. The CR-induced activation of FoxOs implies the resumption of autophagy and mitophagy and the risen expression of antioxidants. CR also evokes activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) that increases the expression of mitochondrial and cell antioxidant enzymes. Any of these processes participates in the CR-related increase in improving healthspan and longevity. Abbreviations: IGF-1, insulin-like growth factor-1; TOR, target of rapamycin; AMPK, AMP-dependent kinase; FoxOs, forkhead box proteins; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species.

Figure 2

Molecular markers of aging involved in the pleiotropic effects of calorie restriction. Several markers characterizing aged cells are indicated by the affected molecules or functions. In the nucleus, aging implies the following: telomeres erosion, genomic instability, and epigenetic alterations (indicated by methylation [m] of histones H [Hm] and DNA [DNAm] or acetylation [ac] of histones [Hac]) with involvement of sirtuins and other modifying enzymes. In the mitochondria, age-related mitochondrial dysfunction leads to reduced ATP production and increased ROS presence. In the cytoplasm, age-dependent proteostasis imbalance causes an abnormal protein turnover with functional consequences. In the cytoplasm, aging also affects other pathways (eg, mTOR, IIS, AMPK, sirtuins, FoxOs) with dual effects namely on metabolism as well as on chromatin remodeling and regulation of gene expression, causing impaired nutrient/energy sensing that leads to different alterations, also due to reciprocal interrelationships. Abbreviations: SIRT, sirtuin; FoxOs, forkhead box proteins; ATP, adenosine triphosphate; ROS, reactive oxygen species; AMPK, AMP-activated protein kinase; IIS, insulin/insulin-like growth factor-1 signaling; mTOR, mammalian target of rapamycin.