Puzzles, promises and a cure for ageing

Abstract

Recent discoveries in the science of ageing indicate that lifespan in model organisms such as yeast, nematodes, flies and mice is plastic and can be manipulated by genetic, nutritional or pharmacological intervention. A better understanding of the targets of such interventions, as well as the proximate causes of ageing-related degeneration and disease, is essential before we can evaluate if abrogation of human senescence is a realistic prospect.

Figure 1. Potentially conserved pro-ageing pathways, their interconnections and possible targets for intervention

In this very simplified depiction, three main pathways, the IIS, TOR and mitochondrial pathway, are indicated. The pro-ageing activities of these pathways are conserved across species, with energy sensors, such as AMPK, as potentially important hubs in the complex networks that integrate them. However, it is important to note potential dissimilarities among species as well. Most, if not all, defects in the mitochondrial respiratory chain are lethal or cause disease in humans, but can increase lifespan in nematodes or yeast. In mammals, mitochondria play an important part in signalling apoptosis, which can either drive or retard ageing, depending on the cell type. There is evidence that many longevity signals converge on members of the FOXO and sirtuin protein families, which can interact. Note that SIR proteins can both activate and repress FOXO. Moreover, the effects of FOXO and SIR2 in cells can be either beneficial (for example, increasing antioxidant defence) or detrimental (for example, apoptosis), and may or may not promote organismal survival. For example, in mammals, SIRT1 dampens apoptosis by repressing FOXO, but also by repressing BAX activation, thereby preventing its oligomerization into the mitochondria outer membrane (cross), which normally triggers permeabilization of the membrane and release of soluble apoptogenic factors, such as cytochrome c, into the cytosol. Apoptosis can be beneficial, for example, by eliminating damaged cells and preventing cancer, or can be detrimental, by eliminating irreplaceable cells, such as neurons.

Figure 2. Balancing somatic maintenance with growth and reproduction may determine lifespan

According to the ‘disposable soma theory’, organisms must compromise between energy allocation to growth and reproduction or somatic maintenance and repair.

Figure 3. The causes of intrinsic ageing

Although ultimately stochastic in nature, the proximal causes of ageing involve both programmed and random mechanisms.