Professor Gary Wittert MBBch, MD, FRACP, FRCP, FAHMS1
1School of Medicine, University of Adelaide
Obesity and a range of lifestyle and health related behaviours interact with genetic factors to determine the risk of chronic disorders such as type 2 diabetes (T2D), cardiovascular disease (CVD), cancer, Alzheimer’s disease (AD), and frailty that occur with increasing frequency with ageing. Mediating mechanisms include insulin resistance, inflammation, DNA damage, and cellular senescence among others. Alterations in male or female specific balance of sex steroids may also be important and there is a bidirectional relationship between increasing obesity with age and changes in sex steroid levels.
There are notable differences in the age-related incidence, and/or overall prevalence of these conditions between men and women. For example, ageing women are at greater risk of AD than are ageing men and coronary artery disease (CAD) and T2D becomes an increasing risk for women after menopause and at a significantly later age than for men. Women with higher “lifetime” E exposure have a lower risk of AD than those with lower E exposure. Loss of ovarian sex steroids at the menopause is also permissive for increasing accumulation of visceral adiposity and more global inflammatory effects than can be explained age or other processes alone.
Metformin, which is of proven efficacy for the management and prevention of T2D has other potentially beneficial effects. It reduces inflammatory processes through suppression of NK-kB, reduces ROS production and limits the negative effects of ceramides. Theoretically therefore, metformin may be of benefit to retard disease processes where the pathogenesis involves inflammation, DNA damage and cellular senescence. Furthermore, metformin may stimulate ischemia-induced revascularisation through an endothelial nitric oxide-synthase dependent pathway, and there are also data to suggest that metformin confers neuroprotection under certain metabolic stressors. In practical terms beneficial effects of metformin include a small, but significant decrease in fat mass and CRP, and improved endothelial function. A reduction in the risk of CV events and death has been demonstrated in patients with T2D with the greatest benefit in those at highest risk. Whether this also occurs in those without diabetes remains unclear. In follow-up of the cohort enrolled in the diabetes prevention program metformin did not have a beneficial effect for frailty or cognitive outcomes.
Whether metformin is of utility to abrogate age related chronic disorders and provide benefit in the management of various cancers will hopefully be determined by ongoing clinical trials.
The benefits of lifelong maintenance of a healthy weight or avoidance of further weight gain, optimal nutrient intake, and regular aerobic and resistance activity are unequivocal and of significant magnitude.
Gary Wittert is a graduate of the University of the Witwatersrand in Johannesburg South Africa. After a year in rural general practice, he trained as an Endocrinologist in Christchurch, New Zealand. His postdoctoral training was at Harvard Medical School and Oregon Health Sciences University. He joined the University of Adelaide in 1994, received a Personal Chair in 2004 and is currently Head of the Discipline of Medicine, Director of the Freemasons Foundation Centre for Men’s Health Research, Senior Consultant Endocrinologist Royal Adelaide Hospital, and Senior Principle Research Fellow at SAHMRI. He has published over 350 research papers and is a Fellow of the Australian Academy of Health and Medical Sciences.