Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include DAF-2 and InR and their homologues in mammals, and inactivation of the corresponding genes is followed by increased life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. The chronic treatment of female transgenic HER-2/neu mice with metformin (100 mg/kg in drinking water) slightly decreased the food consumption but failed in reducing the body weight or temperature, slowed down the age-related rise in blood glucose and triglycerides level, as well as the age-related switch-off of estrous function, prolonged the mean life span by 8% (p < 0.05), the mean life span of last 10% survivors by 13.1%, and the maximum life span by 1 month in comparison with control mice. The demographic aging rate represented by the estimate of respective Gompertz's parameter was decreased 2.26 times. The metformin-treatment significantly decreased the incidence and size of mammary adenocarcinomas in mice and increased the mean latency of the tumors.
Anisimov
Vladimir N
VN
Department of Carcinogenesis and Oncogerontology, N.N.Petrov Research Institute of Oncology, Pesochny-2, St Petersburg 197758, Russian Federation. aging@mail.ru
Berstein
Lev M
LM
Egormin
Peter A
PA
Piskunova
Tatiana S
TS
Popovich
Irina G
IG
Zabezhinski
Mark A
MA
Kovalenko
Irina G
IG
Poroshina
Tatiana E
TE
Semenchenko
Anna V
AV
Provinciali
Mauro
M
Re
Francesca
F
Franceschi
Claudio
C
D000230:Adenocarcinoma / Q000097:blood / Q000737:chemistry / Q000517:prevention & control*; D000375:Aging / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004971:Estrus / Q000187:drug effects; D005260:Female; D053804:Granzymes; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008077:Lipoproteins, LDL; D008136:Longevity / Q000187:drug effects*; D015674:Mammary Neoplasms, Animal / Q000097:blood / Q000737:chemistry / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000235:genetics; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics; D013974:Thyroxine / Q000097:blood; D014280:Triglycerides / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D001786:Blood Glucose; D053804:Granzymes; D007004:Hypoglycemic Agents; D007328:Insulin; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D008687:Metformin; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D012697:Serine Endopeptidases; D013974:Thyroxine; D014280:Triglycerides; D014284:Triiodothyronine; C509214:Gzmb protein, mouse