Healthy ageing: a question of stress, damage and repair. Meeting on mechanisms of biological ageing

Abstract

Meeting on mechanisms of biological ageing

Figure 1

Correlation between stress, damage, ageing and longevity. As discussed at the meeting, oxygen exposure and telomere shortening drive normal ageing processes. When an organism encounters stressful conditions, intracellular damage to various macromolecules may arise, which accelerates the ageing process (upper arrow). However, most organisms have evolved multiple systems to repair and/or eliminate damaged material and hence protect from stress-induced premature senescence (lower arrow). In addition to these environmental factors, several genetic traits predispose individuals to either premature ageing or to a naturally increased lifespan (longevity). While the genetic basis of premature ageing syndromes (such as the Werner syndrome) is well understood, the identity of the genes that specify longevity is largely unknown. Currently, populations of centenarians are being intensely studied to identify longevity-associated human genes.

Figure 2

Molecular events related to normal and stress-induced senescence. Reactive oxygen species (ROS) are capable of damaging both proteins and DNA and are generated in mitochondria, both as by-products and by p66^Shc. Scavenging systems are, however, able to cope to some extent with these agents of damage. For example, superoxide dismutases (SOD1, SOD2) convert superoxide (one type of ROS) to hydroxyl peroxide, which can then be converted to water and oxygen (not indicated in detail) giving rise to a lower ROS load. Moreover, once cellular components such as proteins are damaged (red asterisks) they may be removed and replaced by newly synthesized proteins. This molecular remodelling of the respiratory chain is possible if mitochondrial DNA (mtDNA) is functional. However, during ageing subtle mtDNA mutations and gross mtDNA rearrangements accumulate. Point mutations can be repaired by a repair system (e.g. OGG1) in mitochondria. If functional damage to mitochondria is too severe (e.g. complex IV deficiency), a retrograde response signals to the nucleus and induces the expression of additional genes that can rescue lost functions. This rescue may, at least in some systems, occur via the replacement of the damaged oxidase with an alternative oxidase (AOX) in the respiratory chain, or by a more general change in metabolism. Damage may, however, also lead to the induction of apoptosis via the opening of a permeability transition pore (PTP) in the outer mitochondrial membrane and to leakage of cytochrome c and other proteins (not shown). Age-related changes in the nuclear genome due to damage, methylation or other processes, influence not only mitochondrial pathways but also numerous pathways in the cytoplasm and other cellular compartments (not shown in detail). Repair of nuclear DNA via different enzyme activities {e.g. PARP [poly(ADP)ribosyl polymerase], or WRN, a helicase}, ROS scavenging in the cytoplasm and degradation of damaged proteins via proteasomes consequently have an important impact on biological ageing.

A group of unstressed individuals from different age groups discussed the links between stress and ageing on the Greek island of Spetses, May 18–22, 2002. The conference was sponsored by EURESCO and entitled 'Biological Agening: 2nd EuroConference on Normal Ageing, Longevity and Age-Related Diseases'.