In the early 1990s Cynthia Kenyon and others produced the first C. elegans nematode worms to exhibit significantly extended longevity through a single gene mutation, in daf-2, the nematode version of the insulin-like growth factor 1 (IGF-1) receptor, and went on to map the relevant nearby biochemical landscape of these mutants. It is perhaps overly simplistic to mark this as the dividing line between a research mainstream whose members believed aging to be an intractably complex process, and a research mainstream increasingly interested in slowing aging through adjustment of metabolism, but that is the story as it is commonly told these days.

The mechanisms of longevity enhancement in daf-2 mutants depend on daf-16, a FOXO family transcription factor. The roles of these and other related proteins have been studied intensively in nematodes and other species since the first discoveries. Insulin metabolism - involving insulin, IGF-1, growth hormone, and their cell surface receptors - has emerged as one of the more influential means by which cellular mechanisms determine variations in longevity, both in response to circumstances for individuals within the same species, and to some degree between species. The record for mouse longevity is still held by growth hormone receptor loss of function mutants, for example. These proteins and their relationships are tied to cell growth, nutrient sensing, the calorie restriction response, temperature regulation, autophagy, and many other fundamental aspects of biochemistry.

From a historical perspective, to understand how the research community came to its present distribution of attitudes and focus, it helps to know something about this body of research and its central position in the modern study of aging. It has progressed and grown alongside the slow awakening to view aging as a treatable medical condition. If reliable changes of any sort can be achieved, so the thinking goes, then in principle something can be done to reduce the terrible toll of suffering, pain, and death that accompanies aging. The ability make even small changes means that aging is not intractable. Manipulating insulin metabolism and its surrounding mechanisms, such as through the development of calorie restriction mimetic drugs, is not the future of longevity science, however. It is not a road to rejuvenation, because rejuvenation can only occur when the causes of aging are reversed. All that can be done with the manipulation of insulin metabolism is to modestly slow down aging.

Thus the future of the field, for the treatment of aging at least, will involve a transition away from the study of processes that explain natural variations in longevity between individuals, or due to environmental factors such as calorie intake. A transition away from the work that awoke the possibility of influencing aging, and towards effective means of turning back aging. Since tinkering with insulin metabolism, or any similar approach, cannot produce rejuvenation, other methods must be adopted. This future is best represented by the SENS portfolio, the strategies for engineered negligible senescence, and similar programs focused on repairing the cell and tissue damage that causes aging. This is an entirely distinct focus, orthogonal to topics such as the way in which insulin metabolism functions to adjust the pace of aging. Metabolism generates various forms of damage even when operating normally, and that damage accumulates over time to cause age-related dysfunction, disease, and death. Removing this damage will turn back the state of aging, and thus be a form of rejuvenation.

DAF-16/FOXO Transcription Factor in Aging and Longevity