Treating Metabolic Dysregulation and Senescence by Caloric Restriction: Killing Two Birds with One Stone?

Abstract

Cellular senescence is a state of permanent cell cycle arrest accompanied by metabolic activity and characteristic phenotypic changes. This process is crucial for developing age-related diseases, where excessive calorie intake accelerates metabolic dysfunction and aging. Overnutrition disturbs key metabolic pathways, including insulin/insulin-like growth factor signaling (IIS), the mammalian target of rapamycin (mTOR), and AMP-activated protein kinase. The dysregulation of these pathways contributes to insulin resistance, impaired autophagy, exacerbated oxidative stress, and mitochondrial dysfunction, further enhancing cellular senescence and systemic metabolic derangements. On the other hand, dysfunctional endothelial cells and adipocytes contribute to systemic inflammation, reduced nitric oxide production, and altered lipid metabolism. Numerous factors, including extracellular vesicles, mediate pathological communication between the vascular system and adipose tissue, amplifying metabolic imbalances. Meanwhile, caloric restriction (CR) emerges as a potent intervention to counteract overnutrition effects, improve mitochondrial function, reduce oxidative stress, and restore metabolic balance. CR modulates pathways such as IIS, mTOR, and sirtuins, enhancing glucose and lipid metabolism, reducing inflammation, and promoting autophagy. CR can extend the health span and mitigate age-related diseases by delaying cellular senescence and improving healthy endothelial-adipocyte interactions. This review highlights the crosstalk between endothelial cells and adipocytes, emphasizing CR potential in counteracting overnutrition-induced senescence and restoring vascular homeostasis.

Keywords: adipocytes; caloric restriction; endothelial dysfunction; oxidative stress; senescence.

Figure 1

Hallmarks of a senescent cell. Senescent cells are defined by several key features. First, they exhibit a state of permanent cell cycle arrest, evidenced by p21, and/or p16 expression, and telomere shortening. Second is their morphology changes, becoming enlarged and flattened. Finally, they undergo multiple intracellular modifications, including mitochondrial dysfunction and the accumulation of reactive oxygen species (ROS) as well as damaged proteins and lipids at high levels. Senescent cells have a peculiar senescence-associated secretory phenotype (SASP) program, consisting of multiple cytokines and chemokines, and are positive for the senescence-associated beta-galactosidase (SA-β-gal) protein.

Figure 2

Biochemical pathways involved in endothelial senescence are affected by dietary factors, such as a high-calorie diet and caloric restriction. A high-calorie diet suppresses two critical pathways, essential for maintaining endothelial function: NAD⁺-dependent protein deacetylase sirtuins (SIRTs) and AMP-activated protein kinase (AMPK). Caloric restriction (CR) increases NAD⁺ levels, activating SIRTs. CR reduces ATP levels, leading to an increased AMP/ATP ratio, which activates AMPK and stimulates the autophagic process via ULK1. Additionally, a high-calorie diet activates the mammalian target of rapamycin (mTOR) and insulin/insulin-like growth factor 1 (IGF-1) pathways, which are associated with increased inflammatory responses, the reactive oxygen species (ROS) stress-induced translocation of NF-κB to the nucleus, senescence-associated secretory phenotype (SASP) induction, and dysregulated autophagy. In contrast, caloric restriction exerts protective effects by modulating key intracellular pathways involved in cellular senescence, including AMPK, mTOR signaling, and the IGF-1 axis. These changes promote enhanced DNA repair, lipid metabolism, autophagy, and resistance to oxidative stress.

Figure 3

Adipocyte–endothelial cell crosstalk. Cell-to-cell communication between adipocytes and endothelial cells (ECs) is crucial in maintaining the homeostasis of both tissues and the whole organism. The main actors in this talk are several cytokines that are differentially produced by the two cell types, as well as micro-RNA-carrying extracellular vesicles (EVs). While obesity is linked to an increase in the production of pro-inflammatory cytokines (e.g., TNF-alpha, IL-1β, IL-6) and micro-RNAs (miR) that are involved in boosting endothelial dysfunction (ED) and senescence, caloric restriction (CR) is conversely involved in the upregulation of specific miRs and anti-inflammatory mediators (e.g., NO, VEGF) that are responsible for preserving a healthy EC phenotype.

Figure 4

A timeline of key milestones in caloric restriction research. This timeline outlines key milestones in caloric restriction (CR) research, beginning in 1935 with McCay’s demonstration that CR extends the lifespan in rodents. By the 1980s, the focus shifted to uncovering the molecular mechanisms underlying CR’s effects [217,218,219]. In the following decades, studies have expanded further to nonhuman primates [220], and the understanding of genomic implications [221] and epigenetic effects [222]. An important milestone was the CALERIE (The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy—CALERIE™), the first clinical trial [223] that investigated CR effects in humans. In 2016, the involvement of CR in long non-coding RNAs [224] was initiated. Finally, the effect of CR on telomere shortening was studied in the CALERIE 2 trial [225].