Large increases in the life span of the fruit fly Drosophila melanogaster have also resulted from selective breeding. More recently, genetic engineering techniques have been used to increase fruit fly life span.

Fig Survival curve for a typical Caenorhabditis elegans longevity mutant. Life span is determined in C. elegans by following the survival of a cohort of approximately 100 worms that are synchronously aging. The normal mean life span of C. elegans is 20 days, whereas the long-­lived mutants have a mean life span of 36 days.

Such simple genetic alterations provide a way to uncover the causes of aging. In many cases, the genes determining life span have been identified, and the protein product encoded by the genes has been inferred from the DNA sequence. In C. elegans, a number of gerontogenes are known to be similar to human genes, and remarkable new ways of thinking about aging have emerged.

One genetic pathway that determines the life span of C. elegans is very similar to a pathway that is implicated in the insulin response in humans. When insulin binds to its target tissues in humans, a signal is relayed from the cell surface to the interior, where a succession of metabolic and gene expression modifications take place.

Some gerontogenes in C. elegans encode for protein components of an insulinlike signaling pathway. Reducing signaling through this pathway in the roundworm promotes an increased life span without slowing other traits, such as development. Current experiments are investigating the cellular or hormonal processes controlled by this pathway in the roundworm as well as the influence of this pathway on the aging of other species.

A second class of worm gerontogenes also shares similarity with genes in mammals. The elk, or "clock," genes appear to control the timing of a whole range of biological processes,
including the rate at which the roundworms grow. Mutation of these genes promotes longevity, and at least one of these elk genes encodes a protein involved in regulating metabolism in the mitochondria, the main manufacturer of cellular chemical energy. This may be a genetic clue to one of the major causes of aging-the toxic by-products of metabolism, oxygen radicals. Oxygen radicals

Oxygen radicals are produced in cells, primarily in the mitochondria, as a normal consequence of oxidative metabolism. Oxygen radicals are highly reactive molecules that contain oxygen and are known to cause damage to proteins, DNA, and the lipid bilayer that makes up the cell membranes. Some experiments provide direct evidence for the theory that, over a life span, the accumulation of such oxidative damage compromises cell and tissue function and that the rate of aging is determined by the rate of damage accumulation. All organisms have natural defense systems that counteract the action of oxygen radicals. Without these systems, life in the presence of oxygen would be very difficult.

The defenses comprise a series of small molecules, such as antioxidant vitamins, and enzymes that catalyze the conversion of oxygen radicals to nontoxic molecular species. If aging is caused by reactive oxygen radicals, the genes that encode the antioxidant enzymes may affect the rate of aging. This hypothesis has been tested by genetically engineering fruit flies to carry extra copies of these genes and hence make more antioxidant enzymes. In some experiments these flies were indeed long-­lived.

Nematode worm life span was also significantly increased by feeding the roundworms small-molecule drugs that mimic the action of these antioxidant enzymes. In addition, the roundworm gerontogene mutations in the insulinlike pathway made the worms resistant to oxygen radicals.
This all suggests that oxygen radicals may be important in the aging of a number of diverse animals. But are oxygen radicals important for mammals? A genetically mutant mouse, the p66shc mouse, indicates that they might be. This mouse strain is 30% longer-lived than the similar mouse lacking the mutation. The mutant mice are also resistant to oxygen radicals, and even when cells from this mouse strain are grown in culture, the cells are resistant to chemicals that produce oxygen radicals.

Other factors
Although it appears that resistance to oxygen radicals is a major determinant of longevity, long-lived mutants are also resistant to a range of other stresses. For example, mutation in the nematode worm age-l gene, which encodes for a protein in the insulinlike signaling pathway, confers resistance to oxygen radicals, heavy metals, heat, and ultraviolet radiation. For this to happen, the signaling pathway is probably affecting the levels of not only antioxidant enzymes but also other stress-resistance proteins.

This includes proteins known as molecular chaperones that are generally associated with maintaining other cellular proteins in their correctly folded and active state. Heat stress causes a protein to unfold, and molecular chaperones facilitate refolding or target the damaged protein for degradation. Worms and flies engineered to carry extra copies of genes encoding molecular chaperones also exhibit increased life spans, suggesting that increasing an organism's resistance to various stresses can generally confer longevity.

Fig.Factors affecting aging. Aging may be due to the accumulation of molecular damage resulting from the action of reactive oxygen radicals. Evidence for this mechanism comes from genetic alterations that increase the levels of antioxidant enzymes and appear to promote longevity. Molecular chaperones also promote longevity, by restoring damaged proteins to their healthy folded state.

Human aging
Human aging has also been the subject of genetic analysis, but very little is known of the human gerontogenes compared with the invertebrate counterparts. Longevity studies of twins have found that about 25% of the life-span differences in human populations can be accounted for by genes. Efforts to find these genes are under way, and some success has come from studies of specific genes in centenarian populations.

If a particular form of a gene is associated with longevity, that form should be found more frequently in the centenarian population compared with the genral population. Some studies have shown that one particular variant of a gene called APOE was overrepresented in the centenarian population, suggesting that it contributited to the longevity of this group.

In addition to gene association studies, the human aging genes have been discovered by investigations of rare premature aging syndromes. An example is Werner’s syndrome. This disease occurs in adults and is associated with loss of muscle, premature graying and loss of hair, heart valve calcification, and atherosclerated brain aging. The gene that is altered in Werner’s syndrome has been identified (it is involved in DNA replication), and it is hoped that therapies for the condition may emerge from this work.

The main concern in studies on human aging is not life span so much as the impact that aging has on health. Aging is the most important factor for the onset of disease in developed countries, but link between aging and disease in such as Alzheimer’s is unknown. However, genetic studies are at the hearth of the current understanding of some age-related diseases.

For example of Alzheimer’s disease are familial and are caused by inheriting certain forms of genes. The discovery of Alzheimer’s disease genes has led to the identification of potential causal factors such as the protein Beta-amyloid that is found in deposits in the brains of such patients.