The gerontological saga of antidiabetic biguanides: From ignorance to prudence via high hopes

The history of the discoveries that shaped the current attitudes to the use of antidiabetic biguanides, mainly metformin, as antiaging agents is reviewed. An emphasis is made on the mounting evidence that the diseases of aging including type II diabetes mellitus, the metabolic syndrome, neurodegenerative conditions and cancer that are featured in the clinical trials of metformin are increasingly recognized as those for which physical exercises are effective in risk reduction and therapy enhancement. The known primary molecular targets of metformin map to some of the signaling pathways by which the effects of the two most robust physiological antiaging interventions, i.e. energy consumption increase and calorie intake restriction, are transduced to the cellular and physiological systems implicated in regulating the balance between, on one hand, growth and proliferation and, on the other hand, maintenance and repair. However, metformin and other allegedly antiaging agents can reproduce but partly and in biased ways the effects of the physiological antiaging interventions. In particular, although metformin may help to maintain the current physical conditions, it hampers the gains in physical fitness that are afforded by exercises. These observations should be taken into account in advising metformin to healthy people engaged in increasing their physical fitness by exercises or to patients whose muscular mass is decreased during disease and should be restored thereafter.