Every schoolchild knows that women produce estrogen and men testosterone. So it caused quite a stir when Sundeep Khosla claimed that the female sex hormone prevents men’s bones from weakening as they age. Nevertheless, this theory turned out to be true. The Novo Nordisk Foundation is awarding Sundeep Khosla the 2018 Jacobæus Prize for this and many other pioneering research discoveries on what happens to bones when we age.
The world’s population is getting increasingly older, accompanied by a significant rise in the number of people with such chronic diseases as atherosclerosis and osteoporosis. Researchers from all over the world are therefore attempting to understand the ageing process and how it can be delayed or even reversed. After decades of research, Sundeep Khosla and his colleagues are on the trail of how the body’s signals keep our bones in good shape and how these processes can be recreated as we age.
“We discovered that the level of estrogen regulates both women’s and men’s bones, and then we and others succeeded in delaying the bone weakening by people with a drug that mimics estrogen action on bone. Recent research in this field has provided even more knowledge, and our latest results suggest that we can actually recreate the bone strength we have when we are young so we can entirely eliminate age-related osteoporosis,” explains Sundeep Khosla, Professor and Director, Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota, USA.
Determining bones’ density and destiny
In the late 1980s, when Sundeep Khosla began to investigate bones, the theory was that because estrogen regulates women’s bones, testosterone would similarly influence men’s bones – but something was wrong. Sundeep Khosla stumbled across an article in The New England Journal of Medicine about men with mutations in the genes that produce estrogen, and their bones are very fragile.
“We examined this in greater depth and found that, even though the men’s testosterone levels were low, testosterone did not inherently influence bone strength. In fact, it turned out that a low level of estrogen caused the decline in bone strength. The conclusion was that estrogen has the major influence on bone strength and that treatment with low doses of estrogen can help.”
This remarkable discovery strongly shaped Sundeep Khosla’s subsequent career. He began to examine the importance of other factors than estrogen for the ageing process of bone. This led to many pioneering studies that charted the dynamics and interaction between bone resorption and formation.
“Bones are far from stationary; they are in constant equilibrium between formation, in which the bone cells called osteoblasts continually deposit new material, and resorption, in which the other type of bone cells called osteoclasts break down and release minerals such as calcium into the bloodstream. This equilibrium may shift with age, leading to reduced bone strength and osteoporosis. To delay and reverse this trend, we decided to examine the factors that determine the destiny of osteoblasts and osteoclasts.”
Reversing the ageing process
Many other factors than estrogen levels change and influence our bones as we get older. As a result, Sundeep Khosla and his colleagues decided to examine the entire well-balanced signalling system regulating the formation and resorption of bone. Over time, this balance slowly becomes skewed from damage to DNA or molecular changes that can be caused by the stress to which our cells are subjected throughout our life.
“Cellular ageing is a general process that affects most cells in our body as we age. This process can result from the natural accumulation of genetic changes or the tiny chemical – epigenetic – markers on our DNA that the environment can cause. The ageing of bone cells is often caused by small changes in cellular communication: for example, in the expression of such localized chemical factors as transforming growth factor-beta.”
Transforming growth factor-beta is just one of the bone-regulating proteins researchers have identified in recent years. All these bind to and stimulate stem cells, osteoblasts and osteoclasts to mature. The signals may weaken over time, and the bones do likewise. Ultimately, the osteoblasts and osteoclasts become senescent, which means that they no longer fulfil their usual role in the cells but also fail to die to make room for new cells.
“The ultimate goal is to reverse the ageing process to re-establish the strength of these cells and thereby bone strength among older people who develop these incapacitating bone diseases. Achieving this requires understanding the hierarchical ranking of these mechanisms. This hierarchy can actually help to identify potential therapeutic targets in the ageing skeleton.”
Sundeep Khosla’s longstanding work on ageing bones gained a new perspective and new energy with the 2008 opening of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic in Rochester, Minnesota. This sparked research into how ageing influences the heart and metabolism and not merely bones. The perspectives are enormous, since the researchers hope to be able to regulate some of the fundamental mechanisms related to ageing and thereby delay and treat not only such diseases as osteoporosis and heart disease but also obesity and diabetes.
“All these diseases share the same underlying cause of increased risk – ageing. Our latest results show that medicine can influence signalling and thereby slow the development of some age-related chronic diseases. So far, we have shown that the medicine works on mice, but we are already conducting the first proof-of-concept studies involving people. We hope to market the first products within a few years that can help improve people’s quality of life as they age and also save healthcare systems billions in treating these age-related chronic diseases.”
The Novo Nordisk Foundation has awarded the 2018 Jacobæus Prize to Sundeep Khosla for his enormous contribution to research on skeletal biology and for being an outstanding representative of clinical researchers, including the ability to integrate basic research and clinical applications.