The main objective of aging research is to determine the fundamental processes which explains maximal longevity and to understand the underlying mechanisms of age-related disease processes in hope of preventing debilities which affect the quality of life in old age. Because of this objective, interest has been in the development of biomarkers expedited by a pragmatic interest in establishing reproducible scientific criteria for assessing the effectiveness of interventions that affect aging especially in animal species that have life spans significantly less than that of human. Although many interventions have been proposed, the only one which is currently scientifically valid in altering aging is dietary restriction. Pentosidine is a fluorescent protein cross-link isolated from senescent human extracellular matrix. It is formed through the nonenzymatic reaction of pentose sugars such as ribose with lysine and arginine residues. A more recent study showed that hexoses (i.e., glucose) can form this cross-link. Pentosidine levels are responsive to metabolic conditions which affect life span of humans and animals: a) it is increased in hyperglycemia induced by diabetes, b) it is increased in uremia which kills many rodent species, and c) it is decreased by dietary restriction. We propose to investigate the validity of pentosidine as a biomarker of aging by testing the hypothesis that the rate of accumulation of pentosidine is related to maximum life span of rodent species, and that the genetic susceptibility to uremia will significantly increase, while food restriction will decrease the accumulation rate, respectively. A long-term longitudinal study is proposed by measuring individual rates of accumulation of pentosidine in skin and tail tendons of C57BL/6NNIA mice and Fischer 344 rats fed ad libitum vs. food restricted from early life (3 months) to spontaneous death of each animal. Pentosidine will be measured in tissue biopsies taken every 6 months and correlated with maximum longevity of individual animals. In a further study, pentosidine will be measured cross-sectionally and longitudinally in skin and tail tendons of Fischer 344 and F344/Brown-Norway F1 hydrid representing rat species which are susceptible and resistant to renal disease, respectively. The further objective of this study is to determine the relationship of pentosidine to another biomarker of aging, fluorophore """"""""M"""""""", and to investigate the molecular origin of pentosidine in vivo as reflected by potential precursor sugars in the plasma of food restricted vs. ad libitum fed rodents.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011080-02
Application #
2052291
Study Section
Biological and Clinical Aging Review Committee (BCA)
Project Start
1993-04-15
Project End
1998-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Sell, D R; Nelson, J F; Monnier, V M (2001) Effect of chronic aminoguanidine treatment on age-related glycation, glycoxidation, and collagen cross-linking in the Fischer 344 rat. J Gerontol A Biol Sci Med Sci 56:B405-11
Sell, D R; Kleinman, N R; Monnier, V M (2000) Longitudinal determination of skin collagen glycation and glycoxidation rates predicts early death in C57BL/6NNIA mice. FASEB J 14:145-56
Monnier, V M; Bautista, O; Kenny, D et al. (1999) Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Co Diabetes 48:870-80
Sell, D R; Primc, M; Schafer, I A et al. (1998) Cell-associated pentosidine as a marker of aging in human diploid cells in vitro and in vivo. Mech Ageing Dev 105:221-40
Sell, D R; Monnier, V M (1997) Age-related association of tail tendon break time with tissue pentosidine in DBA/2 vs C57BL/6 mice: the effect of dietary restriction. J Gerontol A Biol Sci Med Sci 52:B277-84
Sell, D R (1997) Ageing promotes the increase of early glycation Amadori product as assessed by epsilon-N-(2-furoylmethyl)-L-lysine (furosine) levels in rodent skin collagen. The relationship to dietary restriction and glycoxidation. Mech Ageing Dev 95:81-99
Sell, D R; Lane, M A; Johnson, W A et al. (1996) Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence. Proc Natl Acad Sci U S A 93:485-90