Progress & Prospects: Gene therapy In Aging

excerpts Gene Therapy (2009) 16, 3–9; doi:10.1038/gt.2008.166     S I S Rattan and R Singh

Studies performed on various experimental model systems indicate that genetic interventions can increase longevity, even if in a highly protected laboratory condition. Generally, such interventions required partial or complete switching off of the gene and inhibiting the activity of its gene products, which normally have other well-defined roles in metabolic processes. Overexpression of some genes, such as stress response and antioxidant genes, in some model systems also extends their longevity. Such genetic interventions may not be easily applicable to humans without knowing their effects on human growth, development, maturation, reproduction and other characteristics. Studies on the association of single nucleotide polymorphisms and multiple polymorphisms (haplotype) in genes with human longevity have identified several genes whose frequencies increase or decrease with age. Whether genetic redesigning can be achieved in the wake of numerous and complex epigenetic factors that effectively determine the life course and the life span of an individual still appears to be a ‘mission impossible’.

Progress

• Biological basis of aging are well understood.
• Prevention is the most rational approach against aging.
• Mutations causing a loss of gene function increase life span in model systems.
• Overexpression of some genes increases life span in model systems.
• Human life span is associated with polymorphisms in genes.
• Several issues concerning gene therapy for extended longevity remain to be resolved.
• Gene therapy in aging also involves epigenetic interventions including stem cells.

Prospects

• The nature and the number of genes and their variants involved in determining the rate of aging and the life span potential of organisms will be determined.
• Experimental model systems will continue to have their use in identifying evolutionarily conserved longevity assuring or gerontogenic pathways; but there will also be human-specific gerontogenic pathways, which remain to be identified.
• The complexity of the epigenetic factors that influence the polygenic traits aging and longevity will be elucidated.
• The realization that aging at the molecular level is a progressive increase in molecular heterogeneity leading to interrupted, incomplete and illegitimate macromolecular interacting networks, will greatly determine what kind of interventions can be feasible or not.
• Gene therapy in aging will require both the prevention of loss of gene expression and the inhibition of gene expression in the right cell types at the right time.
• Understanding the trade-offs between efficient growth, development, maturation and reproduction on the one side and the extended survival of the body beyond the reproductive age on the other will determine the success and failure of potential ant-aging interventions.