Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer.
The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin - the latter with and without rapamycin, and two drugs previously examined: 17-α-estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17-α-estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male-specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α-glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.
Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.|Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Randy
R
Strong
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
Richard A
RA
Miller
Max Planck Institute for Biology of Ageing, Cologne, D-50931, Germany.
Adam
A
Antebi
The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
Clinton M
CM
Astle
The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
Molly
M
Bogue
Max Planck Institute for Biology of Ageing, Cologne, D-50931, Germany.
Martin S
MS
Denzel
Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.|Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Elizabeth
E
Fernandez
The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
Kevin
K
Flurkey
Colorado State University, Fort Collins, CO, 80523, USA.
Karyn L
KL
Hamilton
Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
Dudley W
0000-0002-0079-4467
DW
Lamming
Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Martin A
MA
Javors
School of Biological Sciences, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK.
João Pedro
JP
de Magalhães
Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.|Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Paul Anthony
PA
Martinez
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.
Joe M
JM
McCord
Colorado State University, Fort Collins, CO, 80523, USA.
Benjamin F
BF
Miller
Norwich Medical School, University of East Anglia, Norwich, UK.
Michael
M
Müller
Department of Physiology and Barshop Center for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
James F
JF
Nelson
The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
Juliet
J
Ndukum
Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, The Medical School, The University of Birmingham, Birmingham, UK.
G Ed
GE
Rainger
Department of Geriatric Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK, 73104, USA.|VA Medical Center, Oklahoma City, OK, 73104, USA.
Arlan
A
Richardson
Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.|Department of Biology, MIT, Cambridge, MA, 02139, USA.|Howard Hughes Medical Institute, MIT, Cambridge, MA, 02139, USA.|Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, 02142, USA.|The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, 02139, USA.
David M
DM
Sabatini
Department of Molecular Medicine and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Adam B
AB
Salmon
Center for Basic & Translational Stroke Research, West Virginia University, Morgantown, WV, 26506, USA.
James W
JW
Simpkins
Division of Human Nutrition, Wageningen University and Research Centre, Wageningen, The Netherlands.
Wilma T
WT
Steegenga
Division of Aging Biology, National Institute on Aging, Bethesda, MD, 20892, USA.
Nancy L
NL
Nadon
The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
David E
DE
Harrison
D020909:Acarbose / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005395:Fish Oils / Q000494:pharmacology; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology*; D018737:Hand Strength; D008136:Longevity / Q000187:drug effects*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D045442:Rotarod Performance Test; D020123:Sirolimus / Q000494:pharmacology; D016019:Survival Analysis; D014580:Ursodeoxycholic Acid / Q000494:pharmacology; D000520:alpha-Glucosidases / Q000378:metabolism*
D000975:Antioxidants; D004365:Drugs, Chinese Herbal; D005395:Fish Oils; D065089:Glycoside Hydrolase Inhibitors; D051267:NF-E2-Related Factor 2; C509374:Protandim; D004958:Estradiol; D014580:Ursodeoxycholic Acid; D009637:Masoprocol; D008687:Metformin; D000520:alpha-Glucosidases; D020909:Acarbose; D020123:Sirolimus
17-α-estradiol; NDGA; Protandim; UDCA; acarbose; fish oil; metformin; rapamycin