When faced with questions, modern biological research is greatly equipped to tackle the ‘how’, but often struggles when asked ‘why’.One such classic example is research on ageing. Studies over the last century have established the physiological mechanisms of ageing, with morbid symptoms such as chronic battles against infection, disease, and death. Yet we continue to have very limited insights on why we age. My lab at Ashoka is trying to seek answers through the lenses of evolution and immunology. We think that although ageing is a complex phenomenon with multiple shades, much of its features can largely be explained by mis-regulated immune responses.

At the heart of our hypothesis is natural selection, the key mechanism of evolution developed in the 19th century. We argue that natural selection tightly controls immune responses at a young reproductive age to avoid immune activation at unnecessary levels. A steady decline in reproductive ability with age can cause the process of natural selection to become too weak to effectively control immune responses. As a result, excessive immune responses at inappropriate levels become a common feature in old age, thus causing damage to vital organs. Also, another explanation is that infections early in life manifest damage only at later stages of life, accelerating the ageing process.

In collaboration with Jens Rolff’s lab at Freie Universität Berlin, we have already tested some of these ideas in model insects that share similar immune features with humans. These include mealworm beetles and fruit flies. In a paper published in the Proceedings of the Royal Society B, we, for the first time, pointed out that mounting immune responses are not always beneficial. Instead, their net health impact depends on when and how they are activated (i.e. an individual’s age). For example, young individuals injected with bacterial cell components mounted an immune response that damaged their vital organs and resulted in early ageing with increased death rate. This suggests long-lasting effects of an early-life infection. Whereas, curbing the immune response prolonged their life. Similarly, older individuals infected with a live pathogen lived longer only if their immune response was suppressed. As ageing is a feature of most multicellular life, including humans, we speculate that similar mechanisms also operate in other organisms.

However, many theories remain to be tested. To find more

experimental evidence for our hypothesis, my group at Ashoka is now directly testing the evolutionary outcomes of excessive immune responses with age using the approaches of evolutionary physiology along with experimental evolution. Since tracking evolution in higher organisms is difficult with their complex immune system and long generation cycle, our group uses faster-reproducing insect populations with relatively simple immune systems. With a constant age-specific rise in autoimmune inflammatory diseases such as diabetes, multiple sclerosis, and arthritis in human populations across the globe, our research aims to provide critical breakthroughs in our fundamental understanding of ageing.

As biologists, we cannot ignore the impact that environmental conditions have. For instance, crowding can intensify competition for food, reducing the nutritional intake. It can also increase exposure to pathogens and toxic metabolic waste products, leading to poor hygienic conditions. How does an organism counter such conditions then? One possibility is that under stressful circumstances, organisms can alter reproductive investments to reduce population size. My recent work (with Deepa Agashe’s Lab at National Centre for Biological Sciences), published in American Naturalist, supports this hypothesis. Using red flour beetles we demonstrated that they could significantly reduce their reproductive performance in response to high female numbers in populations. We further discovered that the entire process is chemically controlled. In a dense population, female beetles release toxic ‘quinone’ secretions from their body to communicate to other members so that they all can readjust the reproductive rate to avoid competition for food.

However, biological problems are rarely simple. For example, the same quinones that are used by females for chemical communication under crowding are also potent antimicrobial agents since they can hinder pathogen growth in their surrounding environment. Therefore, the open question that we have is complex and multi-layered – is quinone production a response shaped by evolution to avoid crowding, or to keep the environment free from pathogens. Could it possibly be both? Once again, running long-term evolution experiments may have the answer.