Results: 3

Fig. 3

Fig. 3. Pro-aging and pro-cancer pathways in yeast and mice. From: Calorie restriction and cancer prevention: metabolic and molecular mechanisms.

Similar pathways, including Ras, Tor, S6 kinase (S6K), adenylate cyclase (AC), and PKA, have been shown to promote aging in both yeast and mice. In yeast, CR causes the down-regulation of these proteins, which promote DNA mutations by reducing the activity of stress resistance transcription factors including Msn2/4 and Gis1 and subsequently increasing the level of superoxide and the activity of error-prone polymerases (Rev1, etc). In yeast, this DNA damage-promoting mode can occur largely independently of cell division. In mice, orthologues of yeast Tor, S6K, AC, and PKA promote aging but are also components of some of the most common oncogenic pathways. CR reduces IGF-I and consequently can reduce the activity of protein functioning downstream of IGF-IR including Tor and S6K. Activation of Tor and S6K but also of AC and PKA may promote DNA damage and cancer in part by promoting cell growth and inhibiting apoptosis in damaged cells and in part by promoting aging and genomic instability independently of the rate of cell growth. These pathways may also contribute to cancer and metastases by affecting inflammation and the cellular environment of the malignant and pre-cancerous cells. The mechanisms connecting IGF-I signaling pathways and cancer in mammals are poorly understood but may involve mechanisms similar to those identified in yeast (147).

Valter D Longo, et al. Trends Pharmacol Sci. ;31(2):89-98.
Fig. 1

Fig. 1. Effects of excessive calorie intake and adiposity on hormones and growth-factor production and cell proliferation. From: Calorie restriction and cancer prevention: metabolic and molecular mechanisms.

Excessive calorie intake and a sedentary lifestyle promote hypertrophy of adipose tissue, reduce adiponectin production, and increase circulating free fatty acids (FFA) and inflammation, leading to insulin resistance and compensatory hyperinsulinemia. Increased serum insulin concentration causes a reduction in hepatic synthesis of insulin-like growth factor binding protein 1 (IGFBP1) and steroid hormone binding globulin (SHBG), that leads to increased bioavailability of insulin growth factor 1 (IGF-1) and sex hormones. Adipose tissue is also a major source of extra-glandular estrogens. Chronically elevated circulating levels of insulin, IGF-1, sex hormones and inflammatory cytokines promote cellular proliferation, genomic instability, and inhibit apoptosis in many cell types.

Valter D Longo, et al. Trends Pharmacol Sci. ;31(2):89-98.
Fig. 2

Fig. 2. Mechanisms for cancer prevention by calorie restriction. From: Calorie restriction and cancer prevention: metabolic and molecular mechanisms.

CR causes several key metabolic/hormonal adaptations, that alter the expression of several genes and signaling pathways (up-regulation of certain genes/signaling pathways and down-regulation of others as indicated by the arrows), which produce major cellular adaptations (e.g. a reduction in cell proliferation, increased removal of damaged organelles or cells via autophagy or apoptosis, up-regulation of DNA repair systems and genomic stability) that result in a reduced cancer incidence (see the text). T3 = triiodothyronine; PI3K = phosphatidylinositol-3 kinase; AKT = kinase AKT, also known as protein kinase B; S6K1 = ribosomal S6 protein kinase 1; mTOR = mammalian target of rapamycin; MAPK = mitogen-activated protein kinase; NRF2 = transcription factors NF-E2-related factor 2; SIRT-1 = silent mating type information regulation 2 homolog 1; AMPK = adenosine monophosphate (AMP)–activated protein kinase; FOXO = Forkhead transcription factors; PTEN = phosphatase and tensin homolog.

Valter D Longo, et al. Trends Pharmacol Sci. ;31(2):89-98.

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