An Aging Interventions Testing Program: study design and interim report.
The National Institute on Aging's Interventions Testing Program (ITP) has developed a plan to evaluate agents that are considered plausible candidates for delaying rates of aging. Key features include: (i) use of genetically heterogeneous mice (a standardized four-way cross), (ii) replication at three test sites (the Jackson Laboratory, TJL; University of Michigan, UM; and University of Texas, UT), (iii) sufficient statistical power to detect 10% changes in lifespan, (iv) tests for age-dependent changes in T cell subsets and physical activity, and (v) an annual solicitation for collaborators who wish to suggest new interventions for evaluation. Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen (NFP), 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN), or nordihydroguiaretic acid (NDGA). An interim analysis was conducted using survival data available on the date at which at least 50% of the male control mice had died at each test site. Survival of control males was significantly higher, at the interim time-point, at UM than at UT or TJL; all three sites had similar survival of control females. Males in the NDGA group had significantly improved survival (P = 0.0004), with significant effects noted at TJL (P < 0.01) and UT (P < 0.04). None of the other agents altered survival, although there was a suggestion (P = 0.07) of a beneficial effect of aspirin in males. More data will be needed to determine if any of these compounds can extend maximal lifespan, but the current data show that NDGA reduces early life mortality risks in genetically heterogeneous mice at multiple test sites.
Miller
Richard A
RA
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor VA Medical Center, Ann Arbor, MI 48109-2200, USA. millerr@umich.edu
Harrison
David E
DE
Astle
Clinton M
CM
Floyd
Robert A
RA
Flurkey
Kevin
K
Hensley
Kenneth L
KL
Javors
Martin A
MA
Leeuwenburgh
Christiaan
C
Nelson
James F
JF
Ongini
Ennio
E
Nadon
Nancy L
NL
Warner
Huber R
HR
Strong
Randy
R
D000375:Aging / Q000187:drug effects*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009637:Masoprocol / Q000494:pharmacology*; D051379:Mice; D012107:Research Design; D016019:Survival Analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D003497:Cyclic N-Oxides; C095631:nitroflurbiprofen; C029217:phenyl-N-tert-butylnitrone; D005480:Flurbiprofen; D009637:Masoprocol; D001241:Aspirin