A review of biochemical mechanisms underlying the known approaches to extension of lifespan and/or slowing down of ageing suggests that they all modify balances between generation of active oxygen and carbonyl species and the mechanisms that protect from their damaging effects or repair their consequences. A likely common target of the geroprotector effects of antioxidants, melatonin, and antidiabetic biguanides is the mitochondrial respiratory chain.
Brain aging is associated with a progressive imbalance between antioxidant defenses and intracellular concentrations of reactive oxygen species (ROS) as exemplified by increases in products of lipid peroxidation, protein oxidation, and DNA oxidation. Oxidative conditions cause not only structural damage but also changes in the set points of redox-sensitive signaling processes including the insulin receptor signaling pathway. In the absence of insulin, the otherwise low insulin receptor signaling is strongly enhanced by oxidative conditions.
It was recently reported that the plant polyphenol resveratrol, found, e.g., in grape berry skins, extended lifespan in the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans. This lifespan extension was dependent on an NAD(+)-dependent histone deacetylase, Sir2 in Drosophila and SIR-2.1 in C. elegans. The extension of lifespan appeared to occur through a mechanism related to dietary restriction (DR), the reduction of available nutrients without causing malnutrition, an intervention that extends lifespan in diverse organisms from yeast to mammals.
Trans-resveratrol or (E)-resveratrol [3,4',5 trihydroxy-trans-stilbene, t-RESV or (E)-RESV] is a natural component of Vitis vinifera L. (Vitaceae), abundant in the skin of grapes (but not in the flesh) and in the leaf epidermis and present in wines (especially red wines). In in vitro, ex vivo and in vivo experiments, t-RESV exhibits a number of biological activities, including anti inflammatory, antioxidant, platelet antiaggregatory and anticarcinogenic properties, and modulation of lipoprotein metabolism.
The replicative lifespan of many cell types is determined by the length of telomeres in the initiating cell population. In 20% oxygen, IMR90 cells have a shorter replicative lifespan compared to that achieved in conditions that lower the levels of oxidative stress. We sought to address the role of telomere dynamics in determining the replicative lifespan of IMR90 cells. We analysed clonal populations cultured in parallel in 3 and 20% oxygen. We observed that, at senescence, telomere length was shorter in 3% oxygen and this was proportional to the lifespan extension.
Dietary restriction (DR) increases lifespan in a range of evolutionarily distinct species. The polyphenol resveratrol may be a dietary mimetic of some effects of DR. The pivotal role of the mammalian histone deacetylase (HDAC) Sirt1, and its homologue in other organisms, in mediating the effects of both DR and resveratrol on lifespan/ageing suggests it may be the common conduit through which these dietary interventions influence ageing.
Nihon Rinsho. Japanese Journal of Clinical Medicine
Exciting recent findings are remarkable extension of lifespan of model animals in which single genes are mutated. Studies on model animals have provided valuable as well as limited and often misleading information in understanding human aging and anti-aging practice. It is important to realize that extension of lifespan and retardation of aging processes are two different things in principle, the latter being apparently more important for improving QOL in human. Discussed here are selected topics on the limitation of model animal studies and potential problems of popular anti-oxidants.
A botanical extract (Regrapex-R) prepared from whole grape (Vitis vinifera) and Polygonum cuspidatum, which contains polyphenols, including flavans, anthocyanins, emodin, and resveratrol, exhibited dose-dependent scavenging effects on reactive oxygen species (ROS). The extract inhibited increases of ROS and protein carbonyl in isolated rat liver mitochondria following exposure to 2,2'-azobis (2-amidino propane) dihydrocholoride (AAPH), a potent lipid oxidant generator.
Homeostasis is a key feature of the cellular lifespan. Its maintenance influences the rate of ageing and it is determined by several factors, including efficient proteolysis. The proteasome is the major cellular proteolytic machinery responsible for the degradation of both normal and damaged proteins. Alterations of proteasome function have been recorded in various biological phenomena including ageing and replicative senescence.
Longevity can be explained by the free radical theory of aging, and caloric restriction (CR) studies showed that CR-induced lifespan extension is associated with the prevention of a decrease in oxidative stress. Non-enzymatic lipophilic antioxidants may play a pivotal role in our aging process, and are reflected in our dietary lifestyle and dietary supplementation. Their significance lies in their general good absorption and slow excretion within our body.