EXAMINATION OF TAIL TENDON BREAK TIME: STATUS AS A BIOMARKER OF AGING & GENETIC INFLUENCES
Open Access
- Author:
- Sloane, Lauren Beth
- Graduate Program:
- Biobehavioral Health
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- March 06, 2008
- Committee Members:
- Gerald Eugene Mc Clearn, Committee Chair/Co-Chair
Roger John Mccarter, Committee Member
George Patrick Vogler, Committee Member
Joseph Tobias Stout, Committee Member - Keywords:
- Heritability
Tail Tendon
Mouse
Aging
Quantitative Trait Loci (QTL) - Abstract:
- Tail tendon break time (TTBT) has been considered a biomarker of aging to examine collagen crosslinking changes between strains and species, and also to measure genetic differences with age. Investigation of changes in TTBT with age and genetic influences were examined in two different projects: the Biomarkers of Aging in Mice (BAM) and QTL Analysis of Age-Related Phenotypes (QAARP). The BAM project examined biomarkers of aging (behavioral, physiological and immunological) longitudinally in two generations of a heterogeneous stock (HS) of mice, with measurement occasions at 45, 90, 360, 630, and 900 days of age. Aspects of TTBT that were assessed included correlations across the ages, the relationship with longevity and other biomarkers, and heritability estimates across time determining the genetic influence on TTBT during the lifespan. The QAARP project utilized B6D2F2 animals from a C57BL/6J and DBA/2J cross, and 23 BxD recombinant inbred (RI) strains derived from the same progenitor strains, evaluating a wide array of phenotypes. In this study, examination of TTBT included calculation of heritability estimates for the B6D2F2 and BxD RI animals, a QTL analysis in the same two groups of mice, and further examination of two strains: BxD 8 and BxD 22 with unusual TTBT values. The calculated heritability estimates were extremely low for the HS mice throughout the lifespan, whereas the B6D2F2 and BxD RI animals revealed high estimates of heritability in early life that decreased with age. Furthermore, the correlations of TTBT demonstrated instability across age, which implies TTBT at one time point does not predict subsequent values later in life. The relationships of TTBT with other biomarkers were inconsistent during the lifespan, differing between ages and sexes, indicating changes in developmental processes across time. Data from both studies show that TTBT does not reliably predict longevity. The QTL analysis nominated eight QTLs, two associated with potential candidate genes, and six that may be informative for other genetic factors affecting the extracellular matrix. The BxD 22 RI strain displays TTBT values much greater than the other BxD RI strains, apparently influenced by a single locus. The other outlying BxD RI strain (BxD 8) exhibits a large significant sex difference of increased TTBT occurring between early adulthood and middle-age, suggesting a potential hormonal difference between this strain and the other BxD RI strains. These analyses of TTBT provide evidence for TTBT as a possible measure of functional aging, and as a relatively independent aging process in Comfort’s (1979) hierarchical clock representation of aging.