Genetics of Aging

• Factors related to aging include genetics and mitochondrial DNA damage.

Genetic Variation

• Genetic variation in 'longevity' genes may influence lifespan.
• Single Nucleotide Polymorphisms (SNPs) are variations.
• Each SNP signifies a difference in a single DNA building block, or nucleotide.
• There are 10 million SNPs within the human population, approximately 1 every 300 nucleotides.
• SNPs are a frequent source for polymorphic changes and a major source that distinguishes one individual from another, but it is not the only source of genetic variation.
• Genes are identified in green, SNPs are identified by blue.
• The HapMap project catalogues 10 million SNPs identified in the human genome.

Genotype Influence

• Aging is associated with increased inflammatory cytokines that contribute to age-related disorders.
• Alzheimer's, cardiovascular disease, and arthritis are examples of age-related disorders.
• Interleukin-6 (IL-6) is an inflammatory cytokine, and increased plasma levels correlate with mortality.
• An SNP in the promoter of the IL-6 gene is associated with increased IL-6 and an increased mortality rate.
• Polymorphism is a common DNA sequence variation in a population.

Mitochondrial DNA Damage

• Mitochondria have their own genes.
• Damage to mitochondrial genome occurs 10x more frequently than in the nuclear genome.
• Reactive oxygen species (ROS) generation contributes to mitochondrial damage:
  • ROS includes peroxides, superoxide, hydroxyl radical, and singlet oxygen.
• DNA polymerase gamma replicates/repairs mitochondrial DNA.
• Errors in DNA replication become more frequent with age.
• Accumulating mutations in mitochondrial DNA accelerates aging.
• Aging reduces the effectiveness of DNA polymerase gamma in correcting errors.

Genetic Models

• Mice that are genetically engineered to carry mutations in mitochondrial (mt) DNA polymerase γ (gamma) are a model for aging.
• mt DNA replication is error-prone.
• Proof-reading activity of DNA polymerase gamma is lost.
• Mice show accelerated aging signs evident by 25 weeks, including weight loss, hair loss, curvature of the spine, and reduced lifespan.
• There is a causative link between mtDNA mutations and aging phenotype.
• PolG mice lack mt DNA error correction and show increased mt DNA mutations overall.

Lifestyle Factors

• Healthy aging can be influenced by lifestyle choices.
• Caloric restriction is a 20-40% reduction in daily energy intake without malnutrition.
• Severe food restriction extended lifespan in rats, first reported 1935.
• Caloric restriction has been demonstrated in yeast, worms, fruit flies, mice, rabbits, dogs, and monkeys, but there is no conclusive evidence in humans.
• There are different health or performance responses based off of genotype 1, 2 or 3, depending on how a nutrient affects the SNP.
• Lifestyle intervention, including 150 minutes per week of moderate exercise, following the Food Pyramid, and targeting a 7% initial body weight loss, can blunt diabetes incidence better than medication.
• A study showed a 58% reduction in diabetes incidence with lifestyle changes versus placebo.