molecular basis of lifespan becomes clearer

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A forkhead in the road to longevity: the molecular basis of lifespan becomes clearer.J Hypertens. 2005 Jul;23(7):1285-309. PMID: 15942449

Abstract

Objective: Although the quest for longevity is as old as civilization itself, only recently have technical and conceptual advances in genomics research brought us to the point of understanding the precise molecular events that make us age. This heralds an era when manipulations of these will enable us to live longer, healthier lives. The present review describes how recent experimental strategies have identified key genes and intracellular pathways that are responsible for ageing and longevity.

Findings: In diverse species transcription factors belonging to the forkhead/winged helix box gene, group O (FOXO) subfamily have been found to be crucial in downstream suppression of the life-shortening effects of insulin/insulin-like growth factor-I receptor signalling pathways that, when upregulated, accelerate ageing by suppression of FOXO. The various adverse processes activated upon FOXO suppression include increased generation of reactive oxygen species (ROS). ROS are pivotal for the onset of various common conditions, including hypertension, atherosclerosis, type 2 diabetes, cancer and Alzheimer's disease, each of which shortens lifespan. In humans, FOXO3a, as well as FOXO1 and -4, and their downstream effectors, could hold the key to counteracting ageing and common diseases. An understanding of the processes controlled by these FOXOs should permit development of novel classes of agents that will more directly counteract or prevent the damage associated with diverse life-threatening conditions, and so foster a life of good health to a ripe old age. Just like caloric restriction, lifespan can be increased in various species by plant-derived polyphenols, such as resveratrol, via activation of sirtuins in cells. Sirtuins, such as SIRT1 in mammals, utilize FOXO and other pathways to achieve their beneficial effects on health and lifespan.

Conclusion: Lifespan is tractable and basic mechanisms are now known. Longevity research complements and overlaps research in most major medical disciplines. Current progress bodes well for an ever-increasing length of healthy life for those who adapt emerging knowledge personally (so-called ‘longevitarians’).

Caloric restriction

It has been known for 80 years that enormous increases in lifespan can be achieved in laboratory animals by restricting caloric intake by 30–40%, while maintaining adequate nutrient intake [31–34]. In 25% of rats autopsy has, moreover, failed to reveal the cause of death.

Caloric restriction reduces protein synthesis in liver and skeletal muscle, as well as the load of oxidized proteins [36], owing to faster turnover and thus decreased metabolic toxin exposure [37]. Immune function is enhanced and inflammatory responses of ageing are inhibited [37]. As well, cancer is reduced, accompanied by increased apoptosis (‘programmed cell death’) [37]. Lack of obesity also contributes.

Inflammation is involved in cardiovascular disease, cancers and Alzheimer's disease. Non-steroidal anti-inflammatory drugs can reduce Alzheimer's by 80% [37], as well as cancer risk.

In California, male and female Seventh day Adventists live 7 and 4 years longer, respectively [46], and those who adopt this sect's vegetarian edict have 70% lower fatal CAD risk [47].

Interestingly, calorie restriction initiated in 19-month-old mice began, within 2 months, to increase mean time to death by 42%, with a 4.7 month increase in mean lifespan, a 3.1-fold decrease in age-associated mortality, as well as reduced tumour incidence from 80 to 67% [209]. Hepatic tissue underwent a rapid progressive shift during the 2 months to the same profile seen in long-term calorie restriction [209].