The Promise of a Golden Era for Exploring the Frontiers of Aging, Metabolism and Redox Biology

Abstract

From ancient times to the modern day extending longevity or even finding the elixir for eternal life has been a motivating quest for many civilizations. There are no shortage of Hollywood films and TV series that feature long-lived creatures: some heroes and others villains. Many of the ancient Greeks have what we would regard as a normal lifespan (Montagu, 1994;Batrinos, 2008). For example, Socrates before his untimely demise was in his 70s. Physicians had been directed to concoct potions to extend the life of emperors and the wealthy. In the Qin Dynasty, the emperor sent 500 young men and 500 young women to find the elixir of life in the legendary Penglai, the miraculous place of the immortals. Detailed descriptions of medicines for immortality were written in the book "Essential Formulas of Danjing Classics". Some of these concoctions we would regard as remarkably toxic as they contain mercury or arsenic. Interestingly, this quest for longevity continues unabated and has now become a central pillar for modern health care. However, the perils persist with the unverified claims of a broad range of supplements or the off-target effects of therapeutics which maybe toxic or otherwise decrease longevity. Clearly, then as now an understanding of the fundamental biology and chemistry of aging is an essential goal for modern scientific research.Despite the long history of the fascination of a long life, aging research as a systematic scientific effort is a recent affair. In the United States, the Aging Related Unit in the National Institutes of Health was formed in the 1940s, first in the NIH Division of chemotherapy, then moved to Baltimore City Hospital under the direction of Nathan Shock. In 1974 the National Institute of Aging (NIA) became an independent institute with a focus on aging biology and age related diseases. PubMed documents publications on aging as early as in 1925. In 1988, the first genetic locus age-1 that modulates lifespan was identified in C. elegans (Friedman and Johnson, 1988), and 8 years later cloned and found to encode a PI3 kinase (Morris et al., 1996). Now there are a total of ∼487,000 articles using the search term "Aging" in PubMed, with ∼20,000 articles since 2020.There has also been a long-standing interest associating aging with metabolism. Searching PubMed with "Aging and Metabolism" results in ∼188,685 articles, with 3,219 since 2020. Dietary restriction has been shown to affect longevity and age related illnesses in several organisms and model systems, with the effects on longevity dependent on genetic background (Mair et al., 2003;Liao et al., 2010;Cava and Fontana, 2013). At the molecular level, extended lifespan has been associated with insulin and IGF-1 receptor function, as well as age-1/PI3 kinase activity (Kenyon et al., 1993;Kimura et al., 1997). Modulation of sirtuins, which are NAD+ (Nicotinamide adenine dinucleotide) dependent enzymes, was reported to extend lifespan in yeast (Kennedy et al., 1995;Kaeberlein et al., 1999). AMPK (AMP activated protein kinase), a key sensor...