Taurine, an endogenously produced semi-essential micronutrient, as a regulator of lifespan and healthspan

Summary The age-induced decline in organ functions involves multiple cell intrinsic events. However, and since most physiological processes are orchestrated by extracellular environment, aging is also a consequence of progressive breakdown of extracellular milieu which proffers potential targets for anti-aging therapeutics. Taurine is a semi-essential micronutrient found in organisms across eukaryotic phyla. In mammalian cells, taurine is produced from cysteine by the action of cysteine sulfinate decarboxylase (Csad) and performs a variety of important functions. Taurine can also be obtained from extrinsic sources through a transporter (Slc6a6). Taurine supplementation to young wild-type mice improves, while congenital taurine deficiency due to the lack of SLC6A6, in humans and in mice, impairs functions of multiple organ systems known to be affected during aging. These evidences suggest that taurine may regulate processes associated with aging; however, the effect of taurine on healthspan and lifespan in aged animals, developmental versus postnatal origin, and the underlying mechanisms are unknown. Our preliminary results show that circulating and tissue levels of taurine decline with age in mice, monkeys, and humans. This led us to hypothesize that taurine deficiency is a driver of normative aging. Consistent with this hypothesis, once-daily oral administration of taurine to middle-aged WT mice significantly increases, without any noticeable side effects, in both females and males, the lifespan by 12% and 10%, respectively, and suppresses morbidity. The lifespan extending effect of taurine was also observed in worms suggesting that the effect of taurine transcends the eukaryotic evolutionary landscape to invertebrates. An unbiased association analysis of taurine levels with clinical variables in aged-humans shows that taurine levels associate with several degenerative diseases; and importantly physical exercise, which is known for its anti-aging effects, increases taurine levels in humans. Illustrating the biomedical relevance of above findings, daily oral feeding of taurine to aged-monkeys for 6 months significantly enhanced the functions of several organs. Mechanistically, we find that taurine regulation of healthy lifespan is associated with changes in hallmarks of aging, including a reduction in cellular senescence, increase in autophagy and proteostasis, suppression of mitochondrial dysfunction, and attenuation of inflammaging. In Aim 1, we will determine the degree to which short-term taurine supplementation at mid-life affects aging hallmarks and extends healthy lifespan through transient (3-, 6- or 12-month) and life-long taurine supplementation. In Aim 2, we will determine the effect of developmental versus postnatal taurine deficiency in regulating aging hallmarks, and healthy lifespan through inducible conditional ablation of Slc6a6. In Aim 3, we will begin to identify the contribution of aging hallmarks and upstream mechanisms through which taurine regulates healthy lifespan. Together, our studies are significant as they will establish taurine deficiency as a driver of aging, elucidate its developmental versus postnatal effects, and will identify the mechanisms through which taurine regulates normative aging.