Signs of longevity: look to your proteins
The science of aging and longevity is a complex process, encompassing genetic, lifestyle and environmental factors, with extensive inter-individual variations. Why do some people live longer than others, why do people from particular countries live longer?
It is understood that gene polymorphisms, with minor variations in their sequences, have a major role to play, influencing the immune system and the human metabolism. Genetic studies of old age would reveal those genes associated with longevity but there is another approach, studying proteins, the gene products.
A team of scientists in Japan has undertaken a proteomics study to try and gain an understanding of the molecular mechanisms behind longevity. Tamao Endo and co-researchers from the Tokyo Metropolitan Institute of Gerontology and Keio University School of Medicine undertook a proteomics examination of the plasma from a set of ten female semisuper centenarians, people more than 105 years old.
This age range was chosen on the basis of a report that the human mortality rate reaches a plateau at 105, so semisuper centenarians are the best example of human longevity, having escaped fatal diseases and coped with oxidative stress.
Healthy aging: oxidative stress is a major factor
All of the subjects were deemed to be in good health and were not under acute care or being tube fed. Their plasma samples were pooled to reduce individual variations and they were compared with the pooled samples of healthy 20-39-year old female volunteers.
The plasma proteins were separated by two-dimensional polyacrylamide gel electrophoresis and their gel spots were stained with a fluorescent dye for quantitation by image analysis. There were 18 proteins with different abundances between the old group and the controls, 6 being less abundant and 12 more abundant in the aged samples.
The identities of these differential proteins were probed by mass spectrometry with peptide mass fingerprinting, which allowed 12 of them to be identified.
The protein known as paraoxonase/arylesterase 1 (PON1) was found in reduced amounts in the plasmas from the old subjects. PON1 is an arylesterase bound to high density lipoprotein which hydrolyses lipoperoxides and protects against atherosclerosis by preventing low-density lipoprotein oxidation.
Other published work found that the levels of PON1 fell significantly with age when comparing subjects aged 90-104 years with those of 22-65 and 66-89 years. So, Endo also checked PON1 levels in ten 100-year-old subjects and found them to be the same as those of the semisuper centenarians, implying that the risk of oxidative stress and related diseases does not increase for people once they reach 100 years old.
Three other proteins of interest had increased abundances in the semisuper centenarians. The first was alpha1-microglobulin which suggested that there were increased levels of reactive oxygen species and cell-free haemoglobin, which this protein is programmed to challenge.
The second elevated protein was haptoglobin, an inflammation-sensitive protein, which the researchers thought might be induced for the systemic reduction of oxidative stress. Finally, clusterin precursor levels were also raised, which indicated that the semisuper centenarians had increased levels of oxidative stress.
The discovery that four proteins involved with oxidative stress had altered levels in the subject group compared with the controls is a key finding because oxidative stress is thought to be profoundly involved in the aging process. So, systemic redox regulation is one process that participates in increased longevity among the semisuper centenarians.
Of course, other proteins may also be involved and the research team are currently gathering more semisuper centenarians samples, not a trivial task, to carry out a broader study. Having demonstrated the usefulness of proteomics in gerontology, they will continue to use these techniques in the search for more biomarkers of successful aging.
The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.
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