The bottom line of research on how to extend healthy life is that the length of our life and the time we spend healthy tend to vary together. That is, they improve together. As an example, metformin, a drug used clinically to lower blood sugar in diabetes, prolongs the length of life in the laboratory mouse, delays aging and onset of cancer. Hunger, fasting, or continuous caloric restriction prolongs the life of rodents, as well as the deterioration in the state of muscles and memory, the onset of cataracts and cancer. That is, it prolongs healthy life. When research shows lifespan enhancement it also shows decreased aging  and less risk of disease. As the cascade of causes of death is difficult to establish the question appears of how exactly these factors interact.

Usually it is thought that old age brings disease, and, in fact, old and sick cells are similar in a molecular manner.  Old mice as well as old humans support little deviation from their healthy state before they become sick. Cardiac arrest, delirium, mitochondrial dysfunction, DNA damage, inflammation, abnormal intercellular communication all come more easily in the elderly.

Although this established and intuitive model is quite simple, it is interesting to consider the opposite: it may be that diseases accelerate aging. The metabolic syndrome is already well known to be associated with earlier renal and cognitive dysfunctions, which are associated with periodontal decay and skin inflammation. Chronic obstructive lung disease is associated with renal failure, muscle and cognitive decline. HIV infection and its treatment are associated with premature physical and cognitive loss, vascular dysfunction, and reduced bone density. It appears that age may accelerate diseases which again accelerate aging.

Lifespan is a common measure in studies in laboratory organisms used for screening for interventions. Resveratrol extends lifespan in Sirtuin activity studies in yeast, nematodes, and flies. In mouse studies resveratrol has produced a situations similar to the so-called French paradox: it prevented high-fat diets from inducing insulin resistance, obesity, and disturbances of cholesterol and triglycerides. In nematodes and yeast inhibition of mTOR signaling with rapamycin dramatically extends the length of life of laboratory animals and in research paradigms, delays aging traits, prevents diseases, including neuropsychiatric degeneration, heart failure and obesity. Metformin  activates AMP-activated protein kinase and may serve as a hunger mimetic, and it is being studied for preventing and treating cancer and cardiac disease, even in individuals without diabetes.

As research continues, one of the questions to be considered is whether interventions slow and eventually pause the progress of life or postpone death, or whether they truly affect some intrinsic mechanism of aging. One of the challenges is to distinguish new mechanisms from those like eat-2 or eat-18 mutation, for example, which in nematodes extends lifespan by reducing caloric restriction. Some interventions reduce appetite and make food unpalatable. As the authors mentioned below put it : “Upstream mechanistic research would end up focusing on appetite and food intake control, rather than on pathways of cell dysfunction and health. Well-planned studies address this caveat by measuring food consumption and body weight. Thus, seemingly novel processes or mechanisms identified in lifespan studies may simply point to known interventions”.

Reference (adapted and summarized from, with personal contributions, by Paulo Rogério M de Bittencourt, MD, PhD, FAAN)

Alive and Well? Exploring Disease by Studying Lifespan. Jamie O. Brett and Thomas A. Rando. Institute for Stem Cell Biology and Regenerative Medicine, Paul F. Glenn Laboratories for the Biology of Aging; Department of Neurology and Neurological Sciences; Stanford University School of Medicine; Neurology Service and Rehabilitation Research and Development Center of Excellence; Veterans Affairs Palo Alto Health Care System; Palo Alto, CA USA

Curr Opin Genet Dev. 2014 June ; 0: 33–40. doi:10.1016/j.gde.2014.05.004.

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