People with bad eating habits and irregular eating timings are doing themselves more harm than what they have previously thought. Apart from triggering many metabolic disorders, their wayward lifestyle may be cutting short their lifespan.

Scientists have long known that a gene called sirtuin 1 (SIRT1) — popularly known as the longevity factor — plays a key role in delaying ageing. This gene is known to get activated by reduced calorie intake. However, molecular mechanisms involved in the regulation of the longevity factor were rather unknown so far.

Now, a team of researchers from the Tata Institute of Fundamental Research (TIFR) in Mumbai has shown that glucose derived from food acts as a master regulator of SIRT1. In a paper published in the noted journal PNAS on Tuesday, the scientists led by TIFR biologist Ullas Kolthur-Seetharam found that a byproduct of glucose in the liver binds itself with the SIRT1 protein and modifies it in such a way that it ultimately reduces its activity.

Every organisms, including human beings, go through cycles of feeding and fasting. When they are in a fed state, the body assimilates nutrients from the food to build cellular reserves of fat and glycogen. During starvation, the SIRT1 protein regulates glucose production and fat breakdown in the liver to provide energy to the body.

The study, to which their collaborators from the Indian Institute of Science Education and Research in Pune also contributed, found that both excess and reduced modification of the SIRT1 protein by glucose are detrimental. While no modification causes diabetes and liver inflammation, the excess modification is associated with ageing and obesity.

“Our study shows that bad feeding habits and irregular eating habits would alter this switch and hence affect the activity of the longevity factor. So any diet regime or intervention that maintains the right balance of the SIRT1 activity would lead to better health. This would be mean calorie restriction and regular feeding timings,” Kolthur-Seetharam told BusinessLine.

The findings are important because scientists all over the world have been competing with one another to identify triggers that can activate SIRT1 because of its protective role in a diverse range of diseases such as diabetes, obesity, neuro-degeneration, atherosclerosis, auto-immune diseases as well as diseases that affect kidney and the heart. It is also considered the elixir of life as the protein is found to delay ageing.

India’s dubious distinction

“W hile there is a mad rush to identify therapeutic interventions to activate SIRT1, our study points out that over-activation could be as detrimental. We show that while overactivation of SIRT1 is potentially harmful, sustained degradation is associated with obesity and aging,” said the TIFR scientist.

India has earned the dubious distinction of having the world’s fastest growing diabetic population with an estimated 72 million cases in 2017, a figure expected to almost double by 2025. Increasing evidence indicates that feed-fast cycles are important for healthy living and aberrant feeding (also aberrant fasting) leads to metabolic diseases including non-alcoholic fatty liver disease, hyper-inflammation and ageing.

The liver is one of the central metabolic organs that plays a pivotal role in maintaining organismal health and lifespan and regulates both fat and glucose metabolism, ensuring appropriate utilisation of energy sources during normal fed-fast cycles. Thus, identifying molecular mechanisms within liver cells that regulate metabolic fitness of an organism becomes crucial, “Kolthur-Seetharam said.

The TIFR scientists and their peers elsewhere have earlier shown that the SIRT1 protein has an ability to sense calories. While it is induced upon calorie restriction, its levels (thus activity) decrease in high fat-induced obesity. “In fact, based on our findings, we do propose that meal composition and period of fasting would have a direct impact on SIRT1 activity. Continuous feeding or binge eating will likely decrease SIRT1 and cause accelerated ageing,” Kolthur-Seetharam said.

Metabolic control of the longevity factor that leads to its degradation was unknown until now. Leading pharma companies have been trying to find drugs/nutraceuticals that can activate SIRT1 to treat ageing and age-related diseases. “Our findings are very important in this regard. We believe our study will motivate efforts to identify interventions that result in time/dosage regulated activation of SIRT1,” he said.