A mouse model developed by University of Cincinnati (UC) scientists has aided in the discovery of a protein signaling mechanism responsible for healthful longevity in female mice.
Scientists say the finding offers a potential pharmacological target for achieving protection against age-related diseases.
The research, led by University College of London’s Dominic Withers and co-authored by a team including UC’s George Thomas, PhD, and Sara Kozma, PhD, appears in the Oct. 2, 2009, edition of the journal Science.
In 2004, Thomas, interim director of the UC Metabolic Diseases Institute, led a study that identified the function of protein S6 kinase 1 (S6K1). Normally turned on through a series of reactions initiated by the presence of insulin, it works to drive cell growth. Out of these studies came information about S6K1’s mechanism of action, resulting in a notion that S6K1 is a potential obesity target.
Scientists have long known that the pathway leading to the activation of S6K1 is implicated in life span extension. This phenomenon is very similar to that of a program of caloric restriction: When calorie intake decreases, life expectancy increases.
Armed with this knowledge and an appropriate mouse model for further testing, Withers and his team hypothesised that S6K1 could play a role in mammalian longevity. He began studying this hypotheses using UC’s S6K1 “knock-out” mouse models—those without S6K1.
The team determined that female S6K1 knock-out models were hyperactive and actually consumed more calories, but those calories were quickly used or “burned up,” which naturally lowered levels of ATP (energy) within the cell. Decreased ATP levels in S6K1 knock-out mice increased levels of the protein kinase AMPK, resulting in a restriction of anabolic processes and an increase in longevity.
Not only did the team see evidence of longer life spans with the absence of S6K1, the researchers also observed what they would consider to be very “healthful” lives. Liver profiles were similar to mouse models on caloric restriction alone.
Scientists have yet to determine why their results varied between male and female mice, but the UC team of Thomas and Kozma has previously shown that female S6K1 knock-out models have trouble reproducing.
“This finding is similar to what we know to be true in females on programs of caloric restriction,” says Thomas, professor of cancer and cell biology. “It’s possible that there is an evolutionary explanation for this, and perhaps the inability to reproduce plays a specific role in driving longevity.”
Co-authors include researchers from the European Bioinformatics Institute, National Institute for Medical Research, Imperial College London and the Babraham Institute in the United Kingdom.
Funding support came from the Wellcome Trust, the Medical Research Council, Research into Aging and the Biotechnology and Biological Sciences Research Council.
Release by Wellcome Trust