The cells of the body become damaged as we age, increasing susceptibility to certain diseases. With life expectancy more than doubling in the past century, these diseases are increasingly common leading to a poor quality of life for the elderly. Can we prevent the onset of these age-related diseases?
What is ageing? Ageing refers to the steady decline in the healthy functioning of the human body, such as the ability to fight infections and maintain blood pressure that begins immediately after reaching maturity. The body is comprised of cells, and these cells become progressively damaged as we age which increases susceptibility to certain diseases such as type 2 diabetes, heart disease, cancer and arthritis. With life expectancy more than doubling in the past century, these diseases are now very common leading to a poor quality of life for the elderly. This had led scientists to become increasingly interested in understanding the processes occurring in cells that drive ageing, with the hope that drugs can be developed to prevent the onset of age-related diseases. As we will see, this type of research has implicated the proteins that allow a cell to sense nutrient availability in the process of ageing (1).
It was reported almost 85 years ago that restricting daily calorie intake without any deficiency in the essential nutrients can extend lifespan (2), and remains to this day the only intervention that has been shown to do so across a diverse range of species from yeast to worms, flies, mice and rhesus monkeys. In mice, lifelong calorie restriction extended lifespan by up to 50% (3) and delayed the onset of age-related disorders. However, there are trade-offs to this. For example, the mice were smaller and had a lower core body temperature. Studies carried out over a 25 year period on rhesus monkeys, which have human-like patterns of ageing, provided evidence that calorie restriction reduced the incidence of age-related conditions even in these longer-lived species (4). This implied that calorie restriction may also be beneficial for human health, although there is no data to provide direct evidence of this.
It is now thought that calorie restriction extends life and reduces age-related disease by reducing the growth of cells and instead encouraging the cells to dissemble and rebuild damaged structures within them. By studying yeast and worms that live longer than expected, it was shown that this reduction in growth is by reducing the activity of the nutrient sensors of cells which function to inform each cell how many dietary nutrients are available for them to utilise. Reducing calories is not desirable and perhaps not even healthy for most human beings. Scientists are instead interested in finding drugs that target these nutrient sensors in order to fool the body into thinking that nutrients are scarce without the need to restrict calories.
One of the key proteins that cells use to sense nutrients is called mTOR. This allows the cell to decide whether there are enough nutrients available for the cell to commit itself to growing (building new proteins) and dividing. If the cell decides to grow then repair processes are switched off, meaning that damaged structures in the cell are not removed. If nutrients are always available, the cell therefore never gets the chance to repair itself but is constantly producing new building blocks. However, if nutrients are not abundant then the cell will decide to dismantle damaged structures to release pre-existing building blocks that can be re-assembled to make new structures. By blocking mTOR, the lifespan of mice is extended by promoting this repair process. How are the damaged structures dismantled? This is through a process called autophagy, where damaged structures are isolated in enclosed pouches and then safely chopped up by enzymes created by the cell for this purpose. Rapamycin, an antifungal compound first isolated from soil bacteria isolated from Easter Island, inhibits mTOR. Mice that are given rapamycin experience an extension in their lifespan.
Unlike mTOR which senses nutrient levels, AMPK is a sensor of the energy level inside cells. Inside cells, there are structures called mitochondria that create ATP, which is the energy currency of the cell. When the amount of nutrients is low, less ATP can be made and therefore the energy level inside the cell is low. This is sensed by AMPK, and AMPK then disables mTOR so that it can no longer tell the cell to grow. This promotes the breakdown of damaged structures in the cell by autophagy to provide nutrients that can be used to produce ATP to bring the energy levels back up in the cell.
There is a group of sensors inside cells called sirtuins, which sense the level of NAD+ in the cell. When the nutrient levels are high, cells use NAD+ in order to make ATP and therefore the amount of NAD+ is low. In comparison, calorie restriction leads to an increase in the levels of NAD+, which is detected by the sirtuins. The sirtuins then modify enzymes involved in metabolism in order to make metabolism more efficient, and also activate autophagy. It is known that NAD+ levels get progressively lower with age leading to progressively lower sirtuin activity. One approach is to supplement with a molecule that can be taken up by cells and used to make NAD+, which was shown to extend lifespan and health of mice. There are also Sirtuin activating compounds which activate Sirtuins, such as resveratrol a polyphenol found in red wine.
The pancreas is able to sense the nutrient availability in the blood. Elevation of the nutrient availability from eating a meal is detected by the pancreas leading to the release of a hormone called insulin, the amount released being related to how much the nutrient levels were increased by the meal. The insulin in the blood is then detected by cells using their insulin receptor. This tells the cells to take up nutrients from the blood. This also leads to mTOR telling the cell to grow (produce new proteins) which also prevents autophagy from occurring. Long-lived humans often have changes in their genes, which encode proteins, which make the response to insulin less efficient. This reduces the propensity for insulin to stimulate cells to grow. Metformin is a medication taken for type 2 diabetes. When given to mice long-term starting at 3 months of age, it extends lifespan by 14%. Metformin decreases insulin levels, therefore there is less insulin receptor activity and consequently less stimulation of mTOR. Metformin also stimulates AMPK activity.
(1) Pan, H. & Finkel, T. (2017) Key proteins and pathways that regulate lifespan. The Journal of Biological Chemistry. 292 (16), 6452-6460.
(2) Mccay, C. M., Crowell, M. F. &s Maynard, L. A. (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. Journal of Nutrition. 10 63-79.
(3) Speakman, J. R. & Mitchell, S. E. (2011) Caloric restriction. Molecular Aspects of Medicine. 32 (3), 159-221.
(4) Mattison, J. A., Colman, R. J., Beasley, T. M., Allison, D. B., Kemnitz, J. W., Roth, G. S., Ingram, D. K., Weindruch, R., de Cabo, R. & Anderson, R. M. (2017) Caloric restriction improves health and survival of rhesus monkeys. Nature Communications. 8 14063