Healthspan Extension Research Articles

Use of microarray biomarkers to identify longevity therapeutics

A number of lines of evidence, including nonhuman primate and human studies, suggest that regulatory pathways similar to those invoked by caloric restriction (CR) may be involved in determining human longevity. Thus, pharmaceuticals capable of mimicking the molecular mechanisms of life- and health-span extension by CR (CR mimetics) may have application to human health. CR acts rapidly, even in late adulthood, to begin to extend life- and health-span in mice. We have linked these effects with rapid changes in the levels of specific gene transcripts in the liver and the heart. Our results are consistent with the rapid effects of caloric intake on the lifespan and/or biochemistry and physiology of Drosophila, rodents, rhesus macaques and humans. To test the hypothesis that existing pharmaceuticals can mimic the physiologic effects of CR, we evaluated the effectiveness of glucoregulatory drugs and putative cancer chemo-preventatives in reproducing the hepatic gene-expression profiles produced by long-term CR (LTCR). We found that 8 weeks of metformin treatment was superior to 8 weeks of CR at reproducing the specific changes in transcript levels produced by LTCR. Consistent with these results, metformin reduces cancer incidence in diabetic humans and ameliorates the onset and severity of metabolic syndrome. Metformin extends the mean and maximum lifespans of female transgenic HER-2/neu mice by 8% and 13.1% in comparison with control mice. Phenformin, a close chemical relative of metformin, extends lifespan and reduces tumor incidence in C3H mice. These results indicate that gene-expression biomarkers can be used to identify promising candidate CR mimetics.

Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction

It is widely held that caloric restriction (CR) extends lifespan by preventing or reducing the age-related accumulation of irreversible molecular damage. In contrast, our results suggest that CR can act rapidly to begin life and health span extension, and that its rapid genomic effects are closely linked to its health effects. We found that CR begins to extend lifespan and reduce cancer as a cause of death within 8 weeks in older mice, apparently by reducing the rate of tumor growth. Further, 8 weeks of CR progressively reproduces nearly three quarters of the genomic effects of long-term CR (LTCR) in liver. Fewer of the genomic effects of LTCR are rapidly reproduced by the initiation of CR in the heart, but the changes produced are keys to cardiovascular health. Thus, the genomic effects of CR may be established more rapidly in mitotic than in postmitotic tissues. Most of the genomic effects of LTCR dissipate 8 weeks after switching to a control diet. Consistent with these results, others have shown that acute CR rapidly and reversibly reduces the short-term risk of death in Drosophila to that of LTCR treated flies. Further, in late adulthood, acute CR partially or completely reverses age-related alterations of liver, brain and heart proteins. CR also rapidly and reversibly mitigates biomarkers of aging in adult rhesus macaques and humans. These data argue that highly conserved mechanisms for the rapid and reversible enhancement of life- and health-span exist for mitotic and postmitotic tissues.

Human Genetic Enhancements: A Transhumanist Perspective

1. What is Transhumanism? Transhumanism is a loosely defined movement that has developed gradually over the past two decades. It promotes an interdisciplinary approach to understanding and evaluating the opportunities for enhancing the human condition and the human organism opened up by the advancement of technology. Attention is given to both present technologies, like genetic engineering and information technology, and anticipated future ones, such as molecular nanotechnology and artificial intelligence. 1 The enhancement options being discussed include radical extension of human health-span, eradication of disease, elimination of unnecessary suffering, and augmentation of human intellectual, physical, and emotional capacities. 2 Other transhumanist themes include space colonization and the possibility of creating superintelligent machines, along with other potential developments that could profoundly alter the human condition. The ambit is not limited to gadgets and medicine, but encompasses also economic, social, institutional designs, cultural development, and psychological skills and techniques. Transhumanists view human nature as a work-in-progress, a half-baked beginning that we can learn to remold in desirable ways. Current humanity need not be the endpoint of evolution. Transhumanists hope that by responsible use of science, technology, and other rational means we shall eventually manage to become post-human, beings with vastly greater capacities than present human beings have. Some transhumanists take active steps to increase the probability that they personally will survive long enough to become post-human, for example by choosing a healthy lifestyle or by making provisions for having themselves cryonically suspended in case of de-animation. 3 In contrast to many other ethical outlooks, which in practice often reflect a reactionary attitude to new technologies, the transhumanist view is guided by an evolving vision to take a more active approach to technology policy. This vision, in broad strokes, is to create the opportunity to live much longer and healthier lives, to enhance