Unlocking the Science of Aging: A Conversation with Fabrizio d'Adda di Fagagna

At Clinique La Prairie, we believe that understanding the biological mechanisms of aging is key to unlocking the potential for a longer, healthier life. In this edition of Unlock Longevity, I am honored to speak with Fabrizio d'Adda di Fagagna, a leading researcher whose groundbreaking work explores the cellular and molecular foundations of aging.

As one of the foremost experts on the DNA damage response (DDR), telomere biology, and cellular senescence, Fabrizio has made remarkable contributions to the field of longevity science. His research sheds light on how aging at the cellular level influences overall health and the development of age-related diseases. More importantly, it opens doors to potential interventions that could one day revolutionize how we approach aging itself.

In my conversation with Fabrizio, we delve into the key drivers of aging, the latest discoveries in non-coding RNA and DNA repair, and the exciting possibilities emerging from longevity research.

1.      In your TEDxRoma talk, you discuss the fundamental mechanisms behind aging. Could you elaborate on the key factors that contribute to cellular aging?

Aging at the cellular level is fundamentally rooted in damage to the cell’s most critical and irreplaceable asset—its DNA. When DNA is compromised, the cell launches a sophisticated molecular alarm system known as the DNA damage response (DDR). This response is designed to maintain genomic integrity by halting the cell cycle, initiating repair processes, or triggering programmed cell death when the damage is beyond repair. However, if this response becomes chronic—due to persistent or accumulating DNA damage—it can push cells into a state of permanent arrest known as senescence. Over time, this contributes to tissue degeneration and the onset of aging-related conditions. In essence, the very system that protects us from harm in the short term becomes a driver of aging in the long term.

2.      You mention the significance of telomeres in the aging process. How does telomere shortening impact cellular function, and what are the implications for overall organismal aging?

Telomeres act like protective caps at the ends of our chromosomes, much like the plastic tips on shoelaces that prevent fraying. With every cell division, telomeres naturally shorten, which acts as a kind of biological clock. What’s particularly critical—and concerning—is that telomeres are uniquely vulnerable to damage and cannot be efficiently repaired. This inability to heal makes them a biological Achilles’ heel. As telomeres degrade, they signal to the cell that its genomic integrity is compromised, leading to the activation of the DDR and pushing the cell into senescence. This mechanism directly links telomere attrition to aging and diseases such as cancer and fibrosis.

3.      Your research focuses on the DNA damage response. Can you explain how DDR pathways are involved in aging and their potential role in age-related diseases?

While DNA damage in itself is harmful, it is the cell's response to this damage—via the DNA damage response—that largely dictates the outcome. The DDR is a double-edged sword: vital for safeguarding our cells against mutations and malignancies, but when chronically activated, it can lead to cellular dysfunction. Persistent DDR triggers inflammation, cellular senescence, and apoptosis, all hallmarks of aging. Our findings indicate that aging is not merely correlated with DNA damage—it is driven by it. This ongoing damage and DDR activation are present not just in normal physiological aging but also in a wide range of age-related diseases, such as neurodegeneration, cardiovascular disorders, and cancers.

4.      You highlight cellular senescence as a response to DNA damage. What are the beneficial and detrimental effects of senescence on tissue function and organismal health?

 Cellular senescence is a complex phenomenon with both protective and harmful aspects. In acute situations, such as tissue injury, senescent cells play a vital role by halting cell proliferation and secreting factors that promote tissue repair and regeneration. However, when senescence becomes chronic and these cells are not efficiently cleared from tissues, they secrete pro-inflammatory molecules collectively known as the senescence-associated secretory phenotype (SASP). This chronic inflammation contributes to a decline in tissue function, promotes aging, and increases the risk of diseases such as arthritis, diabetes, and Alzheimer’s. Managing the balance between beneficial and detrimental senescence is therefore key to therapeutic innovation.

5.      Your recent findings suggest a role for non-coding RNAs in activating DDR. How do these RNAs influence the aging process, and what potential do they hold for therapeutic interventions?

 Traditionally, RNA was seen mainly as a messenger carrying instructions from DNA to make proteins. However, we’ve discovered that non-coding RNAs—RNA molecules that are not translated into proteins—play a crucial regulatory role in cellular stress responses. In the event of a DNA break, especially at vulnerable sites like telomeres, specific non-coding RNAs are synthesized at the damage site. These RNAs are not merely byproducts but are active participants in signaling pathways: they facilitate the assembly of DDR proteins and help orchestrate the cell’s response. This opens up an exciting frontier for therapeutics, where targeting these RNAs could allow for selective modulation of DDR, potentially slowing aging and treating related diseases.

6.      Based on your discoveries, what strategies are being developed to manage or mitigate the consequences of aging mechanisms? Are there any promising therapies on the horizon?

Based on our discoveries, we have engineered a new class of molecules capable of selectively inhibiting the DDR specifically at telomeres—the most damage-prone regions of our genome. These molecules effectively reduce the harmful effects of chronic DDR activation without compromising the cell's broader DNA repair capabilities. In preclinical models, we've observed significant reversal and improvement in conditions such as pulmonary fibrosis and age-related immune and blood disorders. These results are incredibly promising and suggest a future where targeted DDR modulation could become a cornerstone of anti-aging medicine. To translate this science into real-world treatments, we founded TAG Therapeutics, a biotech company dedicated to advancing these therapies into clinical use.

7.      What are the next steps in your research on aging and DNA damage response? Are there particular areas you believe hold the most promise for extending healthy lifespan?

Looking ahead, our primary goal is to rigorously test the safety, specificity, and therapeutic potential of our DDR-modulating compounds in a variety of disease models. We are especially interested in age-related diseases such as lung fibrosis and bone marrow failure and we see great opportunities also in the treatment of neurodegenerative conditions like Alzheimer’s disease, where chronic inflammation and DNA damage play a role. By extending our research into new pathological contexts, we aim to validate whether these therapies can broadly enhance healthspan and potentially delay the onset of complex age-related disorders. Our ambition is to not only slow aging but to significantly improve the quality of life during the aging process.

8.      I know that you’re an advocate for working collaboratively (as we know aging research spans multiple disciplines) and disseminating aging research to the public. How do collaborations across fields enhance our understanding of aging, and can you provide examples from your work?

Aging is a multifactorial process that spans genetics, epigenetics, metabolism, immunology, and neuroscience. No single discipline can fully capture its complexity. That’s why collaboration is not optional—it’s essential. Our work has benefited immensely from partnerships with experts in bioinformatics, clinical medicine, pharmacology, and biotechnology. These interdisciplinary synergies have enabled us to accelerate discovery, validate our findings across different systems, and translate basic science into actionable therapies. By bringing together diverse perspectives and expertise, we create a richer, more effective approach to tackling the challenges of aging.

9.      With the above in mind how important is it for scientists to communicate their findings on aging to the public? What role does public understanding play in advancing research and implementing therapies?

Scientific discovery holds little value if it cannot be shared and understood. As researchers, we have a duty not just to our peers, but to society at large, to communicate clearly and responsibly. Public understanding and support are essential for advancing research, securing funding, and accelerating the adoption of new therapies. When people understand the science behind aging, they are more likely to support health initiatives, participate in clinical trials, and make informed lifestyle decisions. Effective science communication also fosters trust, demystifies complexity, and empowers individuals. In short, communication isn’t a side task—it’s a fundamental part of what makes us good scientists.

The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity.

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This article reflects my personal views and is not intended to replace professional medical advice.