Small Steps Towards Exercise Mimetics

Calorie restriction and exercise improve health and longevity to some degree in humans, which makes them topics of interest for the mainstream of aging research - scientists focused on finding ways to permanently adjust human metabolism to slow the damage of aging. Just as investigations into the biochemistry of calorie restriction have produced a field of research aimed at producing calorie restriction mimetics, so too will a greater understanding of the effects of exercise lead into the development of exercise mimetics.

The driving idea here is that people will pay for medical technologies that provide some of the benefits of calorie restriction or exercise without the need for the hard work and willpower involved in the real thing. This seems like a reasonable conjecture, and so plenty of money is flowing into research and development for calorie restriction and exercise mimetic drugs. Where this research starts is the search for genes or proteins that can be manipulated to trigger some of the specific, measurable health or longevity benefits resulting from these lifestyle choices. For example:

Gene alteration in mice mimics heart-building effect of exercise:

By tweaking a single gene, scientists have mimicked in sedentary mice the heart-strengthening effects of two weeks of endurance training ... The genetic manipulation spurred the animals' heart muscle cells - called cardiomyocytes - to proliferate and grow larger by an amount comparable to normal mice that swam for up to three hours a day

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First, they had adult mice swim daily for increasing amounts of time, and after 14 days found that their hearts were mildly enlarged as a result. Other mice with restricted blood flow in their aorta also showed enlargement, but of the type associated with heart disease. The researchers then screened both sets of animals against a collection of all known transcription factors -- proteins that turn gene activity up or down -- and compared their expression in the two types of heart enlargement.

The key differences turned out to be in a pair of transcription factors acting in concert. One, C/EPB-beta, had reduced activity in the exercised mice while the other, CITED4, was more active.

So, could turning down C/EPB-beta in normal mice cause their hearts to grow as if they had been working out - even though they did no extra exercise? The answer was yes: Genetic manipulation to reduce C/EPB-beta expression raised the activity of CITED4, and in those mice, cardiomyocytes began dividing and growing in size until their heart muscles resembled those of the endurance swimmers. The mice also had markedly improved maximal exercise capacity even without exercise training.

Genes produce proteins through the process of gene expression, and the effects of changing the level of expression via genetic engineering can be replicated using designed molecules in a number of different ways. So the next step is typically to seek funding in order to design and test a molecule that can reproduce the observed benefits, and which will later become a drug candidate if successful.