Dr. Nene's wellness story, Ageing secretome research & CAR T-cell anti-ageing therapy
The first issue of our newsletter brings to you a story featuring Dr. Shriram Nene, a research paper of the month, CAR T-cell technology review, and introduces members from the team.
From the Longevity Community
For our first issue, we are excited to feature Dr. Shriram Madhav Nene, a renowned cardiovascular and thoracic surgeon with a medical career spanning over two decades. Born in London and raised in the United States, he trained in General Surgery at UCLA and Cardiovascular and Thoracic Surgery at the University of Florida. A recipient of several prestigious fellowships, his practice areas range from routine and minimally invasive surgery to robotic surgery. Before joining medical school, he was an avid software programmer running his own company at the age of fifteen!
Dr. Nene is passionate about exploring innovative approaches to ageing and well-being, and blending cutting-edge science with practical health strategies. Revisiting his entrepreneurial side, he started a digital media and content company with his wife, Madhuri Dixit, an accomplished actor and dancer.
Read along to know more about his insights on the need for and challenges of adopting a healthy routine, and the future of longevity!
Dr. Nene has been an athlete all along, representing sports teams in high school and college, and continuing to indulge in recreational sport. “For me, Sport is a fitness regime as also a fun-filled pastime.” He is currently developing a technology-driven medical platform committed to healthy longevity.
So, what inspired Dr. Nene to focus on vitality and pursue a wellness-oriented lifestyle?
“As a heart surgeon, I saw many patients who neglected themselves and came in with significant coronary artery disease. While we could save their lives, we could not undo many years of bad living. As a healthcare innovator and influencer, I am trying to lead by example by striving to democratize healthcare for all. Much of my effort is focused on disease prevention, early recognition and early treatment in order to shift the pendulum away from acute disease management and natural history of the disease.”
Talking about wellness hacks that can be a part of one’s daily routine, he believes that the key to wellness lies in a holistic approach and developing a sustainable lifestyle.
“The human body is a remarkable adaptation of genes and responses to the environment. While diet and exercise are critical to preventing disease, the exact regimen depends on each person’s genetic background and lifestyle. Needless to say, adequate sleep, water intake, and mindfulness are critical adjuncts to wellness.”
As sticking to these hacks in a fast-paced, modern world is challenging, he advises us to be clear on what our goals and aspirations are and should be. He says that time is the one commodity that is not fungible, and we need to really hone down on how we should live our lives through each moment.
Speaking about his own challenges, he says, “The specific challenge that I have faced is putting my life on hold while endeavoring to save others. You need to put yourself first and develop healthy lifestyles to overcome the chaotic world you live in. This can be done by sticking to the basics for diet and exercise and then creating a feedback loop to adapt dynamically.”
During his career, Dr. Nene has reviewed a number of papers and research findings related to ageing and longevity. We asked him about his take on longevity research and topics that excite him the most.
“The question of longevity and wellness go hand in hand: we must unlock and understand each person’s code and not practice cookie-cutter medicine. Within this pursuit, there are many manipulations possible. Some of the research coming out on NAD, the role of the mitochondria, telomeres, genes and the proteins they code for, are undeniably exciting. Having said that, we must be critical of the results to provide good evidence-based recommendations and treatment.”
And how does he see the longevity field evolving in a decade?
“As we identify the genes responsible for the essential functions of ageing, and the modulators they create and administer, we will be able to take a closer look at pathology and pathophysiology. The idea would be to create approaches to improving outcomes. The approach could involve genetic interventions in folks with gene-level issues, as also medical approaches with different proven medications that mitigate the effect of the aberrant gene. The ultimate result would be to modify the negative effects of ageing on all levels while avoiding side effects.”
Dr. Nene highlights the need for extensive research in ageing and longevity before recommending one therapy over another. Being a cardiothoracic surgeon and a strong advocate for science-backed, personalized habit-setting, he inspires us to proactively and adopt healthy lifestyles.
Check out his talk on the five essentials for good living on his YouTube channel!
A molecular index for biological age identified from the metabolome and senescence-associated secretome in humans
- Hamsanathan et al., Aging Cell (2024)
There are two types of people in their 70s - Have you ever noticed a stark contrast between individuals who are more youthful and energetic and others who struggle with everyday tasks like climbing stairs or even walking? The reason is that their "biological age" - a measure of how our bodies function—can be quite different from chronological age.
Dr. Aditi U. Gurkar and her team at the Aging Institute of UPMC and the University of Pittsburgh School of Medicine have made exciting progress in understanding this concept. They published a study in May 2024, which analyzed 196 people to find out what makes some age healthily and others age rapidly. They compared two groups: "healthy agers" (75 and older, who can handle physical tasks easily) and "rapid agers" (65-75, who struggle with physical activities).
Here’s what they found:
Basic Metabolism Differences: The study discovered that healthy agers primarily use a pathway for energy production in cells from fatty acids, called β-oxidation. In contrast, rapid agers rely more on ω-oxidation. As these two pathways differ in their efficiencies, ω produces more free radicals inside cells, this shift causes free radical stress at the cellular level, or oxidative stress. Oxidative stress, in turn, speeds up the ageing process; this has been widely studied by many scientists across the world. Healthy agers also had higher levels of beneficial metabolites in their bloodstream like acetylcarnitines, metabolites involved in β-oxidation, and other beneficial compounds, such as β-cryptoxanthin (a vitamin A precursor) and prolylhydroxyproline (good for skin and joints).
They built a Healthy Ageing Metabolic (HAM) Index: As biological ageing cannot be determined by a single metabolic or inflammatory pathway; the study suggests an index of 25 metabolites that can predict biological age. This index shows multiple metabolic and inflammation-related pathways that are different in healthy and rapid agers like those associated with fatty acid metabolism and energy production inside the cell.
Inflammation Markers: Rapid agers had higher levels of inflammation-related proteins. This inflammation contributes to faster ageing and health decline, which has also been widely studied previously.
Gender & Lifestyle Effects: The study also explored further understanding the effect of gender and lifestyle factors like smoking on the above-determined markers of healthy ageing. They found differences between males and females regarding metabolism, but the ageing process was consistent across genders. Notably, the HAM index accurately indicated biological age in both genders. A history of smoking [given up many years before the study] altered specific metabolic markers but didn't significantly change inflammation levels.
How does this study impact on healthy ageing prospects?
The study's significance lies in unraveling the intricate link between circulating factors, metabolism, and biological ageing. It investigates the distinction between chronological and biological age, emphasizing the latter's significance in determining health span. The findings reveal a network of metabolic and inflammation-related pathways that are altered in people who age rapidly or have higher biological age.
Understanding biological age can help us take steps to improve our health span—the period of life spent in good health. Imagine if rapid agers can be identified at an early chronological age and treated with interventions targeting markers of ageing. They can be saved from many age-related diseases, which can improve their health span.
Meet the Scientists
Every issue of the Longevity India Newsletter brings you up, close and personal with the incredible core team driving our mission forward.
In this issue, we’re delighted to introduce a dynamic duo: Prof. Deepak Saini, Convener of Longevity India, and postdoctoral fellow, Dr. Suramya Asthana, Lead Coordinator of this initiative. Let’s take a closer look at their fascinating work and passion areas!
Prof. Deepak, a senior faculty member at IISc, heads the SAInI lab, an astutely coined acronym for Signaling in Ageing, Inflammation & Infection!
What led you into your career in ageing research?
In one word, Serendipity! One of the molecules I worked on in my postdoc days was reported to be enriched in the process of ageing. It all began from there, as I probed deep to find out the ‘why’ and ‘what’ of its impact. And the moment I realized how little we know about ageing, it instinctively became a core theme in my lab.
What are you currently working on?
We are studying a wide variety of fundamental facets of ageing, be it in terms of identifying ageing markers, understanding ageing drivers, developing new ageing models, therapeutics discovery and delivery strategies. Our work is a fine blend of individual and collective explorations. Every student in the lab is working on a different component of ageing biology. At the same time, we are open to collaborations towards unfurling new avenues in ageing.
What is your goal for Longevity India?
This initiative strives to enrich our fundamental understanding of ageing in the Indian context so that we can empower clinical practitioners to address morbidity onset early on, stay healthy for a longer time, and lead a dignified life.
Do you follow any health hacks?
All the mandatory ones! I watch what I eat, sleep well, and keep my gut healthy. I try and steer clear of stress by engaging in meaningful activities, and being in the midst of happy people. Above all, I enjoy what I am doing without worrying about what tomorrow has in store for me.
Dr. Suramya, an accomplished postdoc in the Saini lab currently coordinates clinical and scientific research, along with community and social initiatives for Longevity India.
Why ageing research?
When I joined Deepak's lab, I was working on a very specific cell signalling problem as part of my PhD. However, the answers to that problem unlocked and unleashed the field of ageing for me. I realized that disease onset is nothing but an outcome of fundamental changes within ageing cells, tissues, and organisms. That got me intrigued to dive deep into the fundamental changes at a cellular and molecular level in line with advancing age.
You are currently working on...
I'm the lead coordinator for the Longevity India Initiative, ensuring our initiative keeps growing vigorously and doesn't 'senesce' in any respect! My role involves assimilating and analyzing the scientific studies within the initiative and interfacing with collaborators and funders to keep the momentum going. My interest in the longevity field lies in the hormonal theory of ageing, specially in women’s health, I am actively pursuing research problems in this area.
Your goal for Longevity India...
My vision for the Longevity India Initiative is to shift the country’s approach from merely treating diseases to preventing them. I am more than keen to do my bit towards fostering an environment that recruits and retains top talent within India and promotes advanced, value-added research in longevity.
Any health hacks you follow?
For personal health, I stick to yoga sessions with a trainer; self-discipline with apps was not my cup of tea!
I keep safe distance from social media to the extent possible, choosing instead to immerse myself in reading books, relishing poetry, and exploring new tunes and trends in music.
CAR T-Cells: From Cancer Fighters to Anti-Ageing Agents
In the world of medical technology, few advancements have been as exciting as Chimeric Antigen Receptor (CAR) T-cells. Originally designed to fight cancer, these genetically modified immune cells are now being used to combat another foe: the ageing process itself.
To understand CAR T-cells, think of our immune system as an army, with T-cells as the special forces. Their job is to identify and eliminate threats, like viruses or cancer cells. But sometimes, these threats can hide from our T-cells. That's where CAR T-cell therapy comes in.
Here's how it works:
Extraction: Doctors take some of the patient's own T-cells from their blood.
Engineering: In the lab, they use harmless viruses to insert a new gene into these T-cells. This gene makes the cells produce a special protein called a CAR.
The CAR: Think of the CAR as a high-tech GPS and weapon system for the T-cell. It has two main parts:
An "antenna" (the extracellular domain) that can recognize a specific target on the surface of unwanted cells.
A "trigger" (the intracellular domain) that activates the T-cell to destroy the target cell once the antenna spots it.
Multiplication: The engineered T-cells are grown in large numbers in the lab.
Infusion: The army of CAR T-cells is infused back into the patient's bloodstream.
Action: The CAR T-cells circulate in the body, find their targets, and eliminate them. They can also multiply in the body, creating a long-lasting defense system.
Initially, CAR T-cells were designed to target cancer. Now, scientists are using this technology to target cells involved in ageing. As we age, our bodies accumulate "senescent" cells that release substances causing inflammation and damage to nearby healthy cells.
In a new study, researchers created CAR T-cells with a domain (antenna) that recognizes a protein called uPAR, abundant on senescent (aged) cells. When these CAR T-cells were given to old mice, they hunted down and eliminated aged cells. The mice showed improved metabolism and increased physical fitness. Moreover, when young mice were given these uPAR-targeting CAR-T cells before being put on an unhealthy diet, they were protected from the usual health problems.
Another study used CAR T-cells targeting different proteins called NKG2D ligands. These molecules appear on cells under stress, including aged cells. The CAR T-cells could selectively eliminate aged cells without harming healthy cells, showcasing another potential target for anti-ageing therapies.
The beauty of this approach is its longevity. Unlike drugs that need to be taken regularly, a single dose of these CAR T-cells can patrol the body for months or even years, continuously removing senescent cells as they appear.
As research progresses, scientists may identify more such targets (antigens on the cell) that are specific to aged cells or cells involved in age-related diseases. This could lead to a toolbox of CAR T-cells, each designed to target different aspects of the ageing process in various tissues.
However, challenges remain in translating this to humans. One concern is side effects like cytokine release syndrome, where the immune response causes harmful inflammation. Also, because aged cells are diverse, finding the right "antennas" that are specific enough is crucial. Lastly, the current process of making personalized CAR T-cells is complex and expensive, so making this therapy widely accessible is a significant hurdle.
Despite these challenges, the potential is enormous. By harnessing the power of our own immune system, we might one day be able to slow down or even reverse aspects of the ageing process, helping us stay healthier and more active as we grow older. As this technology advances, the dream of extending our health span moves closer to reality.
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Job Board
Dr. Swaminathan’s lab at IISc is looking to recruit outstanding individuals to his laboratory. This is a unique opportunity for career advancement considering the scientific environment in IISc, and with IISc medical school, India’s first comprehensive physician-scientist program, created to bridge engineering and medicine. Details of the position are as below:
1. Postdoc at RA-I level, requirement : PhD. Ideal candidate would have strong work ethics, communication skills, innovative, diligent and technically strong. Seek individuals with background in 3D culture and animal models. Skillset in Omics and advanced imaging are highly desirable. Experience in kidney research is not mandatory. Interested candidates can contact swami@iisc.ac.in.
