Core to successful aging is delaying the onset of age-related disease (ARD) until late in life. Several hundred genome wide studies identifying associations between ARDs and over 85% of common genetic variation across the human genome have now been published. Most are large-scale, with robust identification and replication of findings.

In reviewing the results, I will address two basic questions:

1. Are the variants identified involved in the key pathways prominent in aging research, especially oxidative stress, insulin, IGF-1 and other endocrine signalling, inflammation, or cell cycle control/cell senescence?

2. Are there variants or loci associated with more than one ARD - loci that might modulate overall aging?

Currently more than fifty variants have already been identified as risk markers for four key age-related diseases, namely cardiovascular disease, type 2 diabetes, osteoporosis and prostate cancer. Many more markers have emerged for other age related cancers and other conditions.

A large number of markers are near or occasionally in genes with known mechanisms relevant to ageing. Most of these are involved in cell cycle control and therefore tissue repair. In addition there are many variants that are very specific to each disease process (e.g.: for diabetes, variants only involved in insulin production). Many of the variants identified are involved in regulatory or splicing roles rather than coding changes to protein sequences. There are also many variants of unknown function, most of which are sited far from the nearest gene in the DNA sequence - these are casting new light on what was previously called "junk DNA".

Thusfar three loci associated with two or more ARDs have emerged. A locus downstream of p16/p15 (CDKN2a/b) contains risk markers for frailty, type 2 diabetes and myocardial infarction. A locus in a "gene desert" contains multiple cancer susceptibilities, with the nearest gene being MYC, also related to cell cycle control. The third shared locus (near TERT), may be involved in telomerase activity and is associated with several environmentally influenced age-related cancers.

These findings suggest that large numbers of cell type specific genetic variations are involved in human ageing, producing a "mosaic" modulation of the ageing process. These cell type specific effects help explain the extraordinary heterogeneity of human ageing, and the difficulties of finding widely applicable biomarkers of human ageing. These findings also confirm the central role of cell cycle and re-growth as a key pathway underlying the human variation in successful ageing. Work is needed to identify more of the many thousands of common and rare variants likely to be involved in successful ageing.