Section 1. Long cycles and lifespans

Numerous primary factors determine lifespans including gene silencing, telomeric activity, nutrition, accumulation of mutations and inadequate body rhythms. Gene silencing is a significant longevity factor in yeast, operated via the Sir proteins (silent information regulator). This gene system is composed of the three genes Sir2, Sir3 and Sir4. It is conserved in many organisms including humans (Guarente and Kenyon, 2000). One action of Sir2 is to silence DNA encoding for ribosomal RNA, which enhances the lifespan. Deleting deacetylase genes also lengthens lifespans in yeast, which also silences ribosomal DNA sequences, although this sytem may be more variable in other species. Silencing may also act indirectly, e.g. the genes HLM and HMR extend lifespan because their simultaneous silencing induces sterility, which triggers longevity. Normal ageing may be due to the slow erosion of Sir2 silencing by stress, although this remains to be shown in mammals.

Several processes influence lifespan in C. elegans including calorie restriction, signalling through insulin⁄IGF‐1, germline activity, the cdk pathway and defective DNA and its repair. Each of these factors can increase lifespans, sometimes by 30%. (Finkel and Holbrook, 2000). Destroying germ-cell precursors extends lifespans by 60%, prompting suggestions that reproductive cyclicity coordinates longevity. Factors such as defective DNA repair, or damage, may be oncogenic and impair longevity (Guarente and Kenyon, 2000). Defective DNA could be identified in a protein interaction map, and RNA interference measured on gene activity. Nutritional effects on lifespans have also been clarified in C. elegans. Metabolic sensors may be involved in genes such as elk in C. elegans, acting via pathways other than daf. They may ‘sense’ mitochondrial function, enabling genes to be set at correct times for behaviour and ageing. Feeding diets lacking coenzyme Q, a lipid with a significant role in aerobic respiration, added 60% to lifespans (Larsen and Clarke, 2002). Coenzyme Q might interact with the daf‐2 pathway in mitochondria, with the enhanced scavenging of reactive oxygen species then extending lifespans. Mice display similar responses, a restricted food intake extending lifespans by one-third perhaps by slowing metabolism and the production of toxic reactive oxygen species (Guarente and Kenyon, 2000).

Telomere clocks measure and may influence longevity. Telomeres have a 5–15 kbp length in human cells, varying between different cell types and between individual chromosomes. Between 50–150 bp of repeat sequences are lost during each cell division. Telomerase prevents this loss by adding repeat sequences, although other mechanisms operate. Shortened telomeres might signify limited lifespans, witnessed in Dolly's arthritis apparently due to early senescence, and positional effects may delay replication of nearby genes. Timing telomere expansion varies on different chromosomes or on the two strands of a single chromosome. They replicate before and during the S phase in human cell lines (Hultdin et al., 2001). Early replication is typical of household and tissue-specific genes, late replication involving heterochromatin and centromeres. Variations arise between patients, indicated by the varying telomere length in their cell samples, although its consequences remain to be clarified.

Longevity is influenced by the actions of some cancer genes, effects sometimes modified by reproductive systems. The p53 tumour suppressor protein plays a significant role, noted in early studies generating mice with modified forms of p53, which were hampered by the onset of early-forming tumours. It seemed that p53 was involved in ageing, a link confirmed by Tyner et al. (2002). They generated mice carrying a normal p53 gene and a homologue with deleted regions in exons 1–6 and some other sequences. The very high p53 activity of these mice led to a high efficiency in tumour suppression, but also to unexpected early signs of ageing. Their skin thinned prematurely, and they developed osteoporosis, organ atrophy and slow wound-healing. p53 had clearly modified various timing systems, possibly including stem cell death in some tissues, the fewer cell numbers then causing the loss of organ homeostasis. p53 also seemed to be involved with telomeres. Shortened telomeres enhance cell senescence and impair proliferation, an effect modified by lack of p53. Cancers might also be involved in gene silencing. Immense care will be needed in making drugs to counteract cancers, in view of the ‘shocking possibility’ that ageing is a side-effect of natural safeguards protecting us from cancer (Ferbeyre and Lowe, 2002).