Achievements

Cellular senescence acts as a brake pedal of the car in our system to avert accidents like cancer: ASU researchers on the quest for a longer life

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Longevity researchers are exploring approaches to fight ageing, including testing a variety of agents that can treat life-threatening human conditions.

Whether it was Ravana, the demon king, who sought immortality; or the asurs and devtas churning the ocean during amrit manthan to produce the elixir of life; or the ancient Egyptians who articulated the desire to live till the age of 120 our mythology, history and culture are full of examples of the quest to live forever.
The quest for longevity has moved beyond living longer, to living disease-free.
Over the last century, innovations in health care have contributed towards enhancing life expectancy. If the invention of vaccines to prevent  life-threatening diseases gave it a boost in the 1950s, improved diagnostic techniques, surgeries and medical advances are leading the fight against fatalities in the 2020s. No wonder, in laboratories around the world, longevity researchers are exploring approaches to fight ageing, including testing a variety of agents that can treat life-threatening human conditions.
A paper published recently in the renowned scientific journal Current Molecular Biology Reports brought out by Springer on the topic ‘The Pivotal Role of Senescence in Cell Death and Aging: Where Do We Stand?’ which included eminent faculty members and students of the School of Biosciences at the Apeejay Stya University as co-authors, reiterates that Senescence plays a significant role in ageing and cell death as well as shows resistance to apoptosis. We interviewed Dr Vyas M Shingatgeri, Dean, School of Biosciences, Apeejay Stya University and Dr. Mohammad Zeeshan Najm, Visiting Faculty, School of Biosciences, Apeejay Stya University, on the important role that senescence can play in stopping injured or cancerous cells from spreading, thereby containing damage within our bodies. Edited excerpts:
 
Please explain the concept of senescence and cell death and its interrelation with ageing and mortality for our readers?
In layman’s language, senescence is the cessation of cellular functions i.e., the cell is alive but because of the signals received, it no longer is able to perform its normal functions and is on the road towards cell death. This also happens during ageing, progressive degeneration of a cell due to multiple causative factors, leading to senescence. These changes leading to senescence also occur in those cells that have undergone abnormal changes which might lead to damage to other cells and to the tissue or organs which might result in abnormality or disease and if such cells undergo senescence this will be an advantage. Such senescent cells aggregate to larger extent as we grow and become older and we define such changes as degenerative changes and the tendency of such cells accumulating to larger extent at younger age indicates a lot of stress factors and can result in early aging in the individuals.
 
As you say in your paper, how can cellular senescence act as a brake pedal of the car in our system to avert accidents like cancer?
Senescent cells do not proliferate but can release molecules which may damage the neighbouring tissue and might lead to diseases like cancer. Senescence prevents proliferation and hence progression, hallmarks of cancer cells, but the cancer therapy might itself lead to senescence. When cells are hurt beyond repair, they can enter a protective state known as senescence, in which they cease dividing. At the same time, the cell begins a pre-programmed self-destruct sequence known as apoptosis. This selfless act prevents injured or cancerous cells from spreading, containing damage within our bodies. For example, if the unrepaired cells enter in the forward process, it can lead to cancer. So, in a nutshell, senescence can avert diseases such as cancer. Senescence is a multi-factorial, complex process, which is a poorly understood field and a lot of research is going-on. Nevertheless, targeting these senescent cells might have huge therapeutic potential.
 
What are the latest research findings and advancements with regards to emergence of senolytic drugs for the eradication of senescent cells and induction of senescence in HIV-infected patients due to HAART drugs? What is their implication for common people?
As discussed above, even in HAART (Highly active antiretroviral therapy) HIV-infected patients, cells undergo senescence, they do not die but become inert, which is a huge threat to our system. In recent years, senotherapeutics, a new class of drugs that selectively kill senescent cells (senolytics) or suppress their disease-causing activity, have been developed to counteract the effect of aging. Dasatinib, an anti-cancer drug which is actually a kinase inhibitor, works by blocking the action of an abnormal protein that signals cancer cells to multiply. Quercetin is another drug which acts like antioxidants to arrest inflammation and is also sometimes used as a senolytic. Similarly, many other antioxidants are used for the said purpose. There are many other drugs or therapeutic agents which are currently under investigations for reduction in the load of such senescent cells. Senolytic drugs specifically target the senescent cells and eliminate them. It hasn’t yet reached the clinical stage, but the research is promising.
 
Are Indians living longer than before? And does a higher life expectation also mean you will be living healthier?
Life expectancy in India has increased over the years with men living longer by 6.9 years and women by 10.3 years. However, latest data on life expectancy between 1990-2013 also shows healthy life expectancy didn’t increase as much: men gained 6.4 years and women gained 8.9 years. The lifespan has certainly increased, but the goal is to achieve enhanced health span, a disease-free lifespan. Data clearly indicates the increase in the life span of both the genders which certainly is being attributed to the current research in the health care and availability of quicker diagnostic tools as well as the therapeutic agents. The current lifestyle of human beings changed so drastically, which has also increased an extra load of stress which is directly or indirectly influencing the release of the agents which signal the  cells into senescence. Hence, the idea or goal is to increase the healthy life span and the research currently even in many research institutes are being directed towards dealing with this issue. Improving lifestyles with the help of alternative science that talks about meditation or breathing exercises to help reduce such cells is also gaining attention to improve life expectancy.  
 
What role does senescence play in aging and cell death as well as resistance to apoptosis and cancer prevention?
Ageing is a process of progressive degeneration of living cells, which would eventually lead to death. In aging, cells senesce, they neither proliferate nor undergo apoptosis but that doesn’t mean they prevent cancer. Apoptosis is actually a programmed cellular death and normally occurs and is good for the cell’s health especially in the proliferative cell types. Senescence; though is a progressive degenerative change it does not die immediately but further process of dividing or proliferating capability is being at halt and hence occurrence of such process in the mutated cells or cancerous cells may be good however they are also the one responsible for the damage as is being seen in HAART treated HIV patients. Therefore, in short if I would like to put this then – Senescence and cancer share similar cellular processes and complex interactive networks, which are still being understood.
 
Each time a cell divides itself, the cell copies the chromosome’s DNA and the telomeres get shorter. When they get too short, the cell can no longer divide. So, it becomes inactive or “senescent” or it dies. This shortening is associated with ageing, cancer, and a higher risk of death. How does present-day research into genetics minimise this?
Telomerase is an enzyme which maintains the telomere length, which is active during in-utero development. In adults, they are active only in germ cells and stem cells, but intriguingly, they are also active in cancer cells.  Shortened telomeres increase the risk of cancer, heart disease and other chronic diseases. There’s still debate, but evidence is growing that their shrinking can cause disease, with the disease process also accelerating the shrinkage. Also, research shows that those with higher levels of antioxidants such as Vitamin C, E and selenium tend to have longer telomeres. Fruits and vegetables are the best sources of antioxidants, which is why a plant-based diet is highly recommended. Re-activating telomerase might offer the possibility of extending the process of ageing and active research is going-on in this direction. But one must tread this path with caution as it is also active in tumour cells. Using alternative therapy and the use of antioxidants that have suddenly grown, needs a thorough investigation. Scientifically using these tools and correlating them to the aging process might shed a greater light and seems to me that such research is being done globally.  
 
Laura C Carstensen, director of the Stanford Centre on Longevity, says longer life is a remarkable achievement but now we need to apply what we are learning to accommodate longer lives. “We need to find cures for Alzheimer’s disease and arthritis, develop technologies that render many age-related frailties invisible…and begin seriously rethinking cultural norms, such as the timing of education and retirement,” she wrote in an article on “Issues in Science and Technology” a few years ago. How far have we progressed on this?
Certainly, with the developments in science and technology, the lifespan has increased. But as mentioned earlier, our ultimate goal is to achieve healthier longevity and have a long way to go. Apart from just focusing on increasing the life span we also should put more emphasis on utilising today’s technology to treat various age-related diseases. Previously the research was only done in the research institutes but now the lifestyle diseases have increased, and it seems even the pharmaceutical and other organisations are funding research on age-related diseases, which can certainly help to answer the issues associated and help to resolve this enigma.

“When cells are hurt beyond repair, they can enter a protective state known as senescence, in which they cease dividing. At the same time, the cell begins a pre-programmed self-destruct sequence known as apoptosis. This selfless act prevents injured or cancerous cells from spreading, containing damage within our bodies.”

Dr Vyas M Shingatgeri, Dean, School of Biosciences, Apeejay Stya University

Life expectancy in India has increased over the years with men living longer by 6.9 years and women by 10.3 years. However, latest data on life expectancy between 1990-2013 also shows healthy life expectancy didn’t increase as much. The lifespan has certainly increased, but the goal is to achieve enhanced health span, a disease-free lifespan.”

Dr. Mohammad Zeeshan Najm, Visiting Faculty, School of Biosciences, Apeejay Stya University

When you are looking beyond life expectancy, the best interventions are exercise and fasting: Singapore-based researcher on ageing

Recent research in eukaryotic model systems from single-celled yeast to nematode worms, fruit flies, mice and humans, has shown that ageing mechanisms are conserved and delaying ageing is feasible by interventions including caloric restriction and drug administration

Mohammad Alfatah, Principal Investigator, Aging Biology Intervention Research, Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR)

Ageing is the biggest risk factor for several human chronic disease, including cancer, neuro-degeneration, heart disease, diabetes, cognitive impairment and immune system decline, says Mohammad Alfatah, the Singapore-based Principal Investigator with the Aging Biology Intervention Research, Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR).

Ageing is characterized by a progressive loss of physiological integrity, cellular functions and metabolic signalling. Such biological changes eventually lead to the prevalence of age-related pathologies. Recent research in eukaryotic model systems from single-celled yeast to nematode worms, fruit flies, mice and humans, has shown that ageing mechanisms are conserved and delaying ageing is feasible by interventions including caloric restriction and drug administration.
The goal of Alfatah Lab is to discover novel interventions for prolonging disease-free life through leading research in ageing biology. The lab’s expertise is in functional biology, chemical genetics, and high throughput screening for several phenotypic and experimental conditions.
The lab identifies anti-ageing compounds by screening the small molecules, natural products, and FDA-approved drugs repurposing. The anti-aging compounds identified from the screen are further characterised to understand their mechanism of action by testing the effect on the known hallmarks of ageing, such as nutrient signalling, oxidative stress, autophagy, mitochondrial integrity, cellular senescence, telomere attrition and genome stability as well as functional analysis to uncover the genes, proteins, and biological processes involved in ageing interventions.
Senescence is actually good for cells, says Alfatah. “When any abnormality happens in cells and the functions decline, there is a mechanism called autophagy which kicks in. Autophagy is the body’s way of cleaning out damaged cells, in order to regenerate newer, healthier cells.  This can lead to a complication in cancer patients. When cancer patients are called for chemotherapy, through specialised drugs or radiation therapy. These attack all the cells and not just cancerous cells.  Some of the cells bypass this targeting and form senescence. They are at a dormant stage. Some cancerous cells also become senescent. They are unaffected by the attack from the treatment and may also lead other ‘normal’ cells to becoming senescent. So, these cells become problematic in the treatment of cancer through drugs. A solution is emerging in the form of Senolytics, a category of drugs that selectively clear senescent cells. Senolytic drugs such as Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using a hypothesis‐driven approach.
Alfatah’s research is based on prevention and not cure, he explains. “As researcher on ageing I am talking about making ageing healthy. Those scientists who look at diseases such as cancer, Alzheimer’s, diabetes etc. are only looking at curing the diseases. As a biology researcher I don’t think about the chronological age but the age of the cells. Older people are more vulnerable because their cells are weak. Even after getting a vaccination, it may not be effective in the absence of new cells that are essential to produce antibodies.”
An elderly man may be very active and can run as fast as a 40 year old despite being chronologically 70 years old? What is an explanation for this? “When we are looking beyond life expectancy and making evolution healthier, two of the best interventions are exercise and fasting,” says Alfatah.
As a researcher he looks at what actually changes at the cellular level when one exercises. “What are the chemical changes that take place? We may look at an experiment in which we can look at two mice: One trained to exercise and one not trained to exercise. Such experiments are already going on in Singapore and California. At the human population level, researchers are looking at those who exercise for one or two hours, above the age of 40 and those who don’t. When we exercise what actually changes in the cells? Those mice who exercise are rich in chemical ‘X’. I will identify that chemical using chromatography, a technique for the separation of a mixture and only feed the mice with that chemical and see the answers. In the experiment, I will feed the mice with only that chemical and not anything else and see the answers.”
Suppose we see that one chemical is present in high quantity in the blood samples of all those mice who have exercised. “Once that chemical is identified and popularised the way aspirin was, it can be given to people who cannot exercise but want to stay healthy. Because what is our ultimate objective of exercise? It is to make our cells healthy. If our cells are healthy, there cannot be any attack on any disease.”
There are lots of anti-ageing compounds available. “Until now everybody says go for turmeric but we don’t really have a scientific mechanism for that. But three compounds, present in rapamycin, resveratrol and blood transfusion/circulation have the most potential. Say my mother is not well and I ask her if I can transfuse my blood to her. One of the research papers says that if you transfuse blood from young mice to old mice, that mice become healthy. That means something is there and there is a chemical basis to it. This could have implications for humans as well.”

Aasheesh Sharma is a seasoned journalist with an experience of more than 25 years spread over newspapers, news agencies, magazines and television. He has worked in leadership positions in media groups such as Hindustan Times, India Today, Times of India, NDTV, UNI and IANS. He is a published author and his essay on the longest train journey in India was included in an anthology of writings on the railways, brought out by Rupa Publications. As the Editor of Apeejay Newsroom, he is responsible for coverage of the latest news and developments in the Apeejay institutions. He can be reached at [email protected]

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