One of the paradoxes of longevity research has been the observation that persons of exceptional longevity actually have more disease-related genes in their genome than ordinary people. Intuitively, one would expect just the opposite, that the lack of disease-related genes would explain their increased lifespans. Although they have a higher than normal incidence of genes known to be associated with disease conditions, they appear to have some kind of innate protection against the effects of those genes. A hypothesis explaining this apparent paradox was proposed, and experimentally validated in a study of Ashkenazi Jewish centenarians who participated in the Longevity Gene Study at the Albert Einstein College of Medicine. Apparently, certain longevity genotypes “buffer” or cancel out the effects of harmful genes, allowing them to accumulate.
Buffering Mechanisms in Aging: A Systems Approach Toward
Uncovering the Genetic Component of Aging:
“We corroborated this hypothesis by studying gene–gene interactions between age-related disease genotypes and longevity genotypes. Our findings suggest that individuals with the favorable longevity genotype can have just as many deleterious aging genotypes as the rest of the population because their longevity genotype protects them from the harmful effects of the other. We identify genes contributing to extreme lifespan as well as their counterpart, age-related disease genesAs an example of this buffering mechanism, they found, for instance, that a SNP of the CETP gene I405V protected against the effects of disease-causing LpA gene. SNP, or Single Nucleotide Polymorphism means that an amino acid substitution is found in a single base-pair of a gene. In this case, isoleucine is substituted for valine in codon 405 of the gene encoding CETP (Cholesterol Ester Transfer Protein). This genetic variant is referred to as CETPVV when individuals are homozygous, which means that both chromosomes have the same SNP. LpA is the gene for a lipoprotein that predisposes carriers for heart disease.(ref) It was previously known that CETPVV was associated with exceptional longevity.(ref) Individuals with CETPVV have abnormally large lipoprotein particles (both HDL and LDL); and they have lower rates of cardiovascular disease and metabolic disorders. They also have lower rates of cognitive decline.(ref) From a more recent study published in the JAMA in 2010:
“We found that people with two copies of the longevity variant of CETP had slower memory decline and a lower risk for developing dementia and Alzheimer’s disease,” says Amy E. Sanders, M.D., assistant professor in the Saul R. Korey Department of Neurology at Einstein and lead author of the paper. “More specifically, those participants who carried two copies of the favorable CETP variant had a 70 percent reduction in their risk for developing Alzheimer’s disease compared with participants who carried no copies of this gene variant.” (ref)
Will the next generation of CETP inhibitors provide protection from cognitive decline and increased lifespan, as well as protection from cardiovascular disease?
Not necessarily. Remember the longevity gene CETPVV does not prevent expression of CETP; it alters the expression of CETP in ways that are not yet fully understood, and may be difficult to mimic pharmaceutically. Some type of gene therapy which inserts the CETPVV variant, using an adenovirus or stem cells might be a possible alternative treatment strategy. This transport protein is known to play a vital role in both the intra- and extra-cellular transport of lipids. For example, cholesterol and triglycerides are synthesized within the endoplasmic reticulum; however, they are metabolized and stored in other cellular compartments. Evidence suggests that by interfering with the normal intracellular transport of lipids, inhibiting CETP could cause abnormal intracellular fat distribution accompanied by ysfunctional lipid metabolism and energy storage. Fat cells are not merely fat storage depots, but actively secrete many signaling hormones, known as “adipocytokines.” Abnormal adipocytokine secretion is associated with numerous health problems, including heart disease, diabetes, obesity, etc.
Possible Role for Intracellular Cholesteryl Ester Transfer Protein in Adipocyte Lipid Metabolism and Storage:“The newly discovered secretory functions of adipocytes have shifted the view of adipose tissue from being a simple energy storage tissue to one where this tissue functions as a major endocrine organ. In addition to their cholesterol and TG storage function, adipocytes also synthesize and secrete a variety of factors, such as leptin, adiponectin, angiotensinogen, resistin, and lipoprotein lipase, that regulate whole body energy balance and lipid homeostasis (59, 60). The secretion of these factors is closely linked to the lipid status of adipocytes. Both hypertrophy (excess of lipid content) and hypotrophy (low lipid content) of adipocytes have been shown to disrupt the secretion of these factors and cause abnormal whole body metabolism and inadequate insulin responsiveness (59, 60). Our studies demonstrate that CETP deficiency leads to abnormal TG and cholesterol storage and lowers the membrane ratio of free cholesterol/protein, factors reported to be associated with induction of insulin resistance and alteration in the synthesis of adipocytokines (44). Our findings, if they can be extrapolated to adipose tissue, suggest an important role for CETP in regulating the multiple functions of adipocytes.”
For a more in-depth discussion of CETP longevity variants, see Dr. Guiliano’s earlier entry: CETP Gene Longevity Variants.