The Hallmarks of Aging - Part 3 of 3

In this third part of the newsletter, we continue our exploration of the Hallmarks of Aging, diving deeper into the mechanisms that shape the aging process. Aging is a complex biological process driven by key mechanisms identified in The Hallmarks of Aging, a groundbreaking framework inspired by The Hallmarks of Cancer. Originally published in 2013 and updated in 2023, this model classifies 12 hallmarks into three categories: Primary (damage drivers), Antagonistic (responses that turn harmful over time), and Integrative (systemic consequences of accumulated damage).

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In the first part of this journey, we explored Genomic Instability—the accumulation of DNA damage leading to cellular dysfunction—and Telomere Shortening, where protective chromosome caps erode, triggering cellular senescence and inflammation.

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In the second part of the “hallmarks” newsletters, we delved deeper into the intricate mechanisms that shape the aging process, uncovering five more hallmarks that play a critical role in longevity.

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We began with Epigenetic Alterations, the subtle yet powerful shifts in gene regulation that accumulate over time, influencing how our cells function and respond to stress. From there, we explored Loss of Proteostasis, where the body’s ability to maintain and manage proteins falters, leading to the buildup of toxic or misfolded proteins that disrupt cellular health.

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Our journey then took us to Macroautophagy, the essential cellular recycling process that clears out damaged components. With age, this system slows down, allowing waste to accumulate and impairing the body's ability to renew itself. We also examined Deregulated Nutrient Sensing, where the once finely tuned mechanisms that regulate energy and metabolism become less efficient, contributing to metabolic imbalances and age-related diseases.

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Finally, we uncovered the profound impact of Mitochondrial Dysfunction, a hallmark that affects the very core of cellular energy production. As mitochondria deteriorate, they produce less energy and more harmful reactive oxygen species, setting off a cycle of damage that accelerates aging.

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With each hallmark we explore, the bigger picture of aging becomes clearer. In this edition, we will complete the journey by examining the final five hallmarks—revealing how cellular senescence, stem cell exhaustion, disrupted intercellular communication, chronic inflammation, and dysbiosis all contribute to aging.

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The 8th hallmark of aging is “cellular senescence”, a process triggered by factors like genomic instability, telomere dysfunction, and mitochondrial damage—all hallmarks we’ve discussed before. This hallmark, known as an “antagonistic hallmark,” represents a key mechanism in the biology of aging. Cellular senescence has been extensively studied by Judith Campisi at the Buck Institute in California, an institution founded in 1999 (now under the leadership of my friend Eric Verdin), where her research has provided invaluable insights into its role in aging and longevity.

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As we’ve previously discussed, senescent cells are those that have entered a state of “altered” metabolism. These cells are still alive but unable to perform their normal functions. They can be easily recognized under a microscope due to their distinct characteristics: they appear enlarged, misshapen, and irregular. Senescent cells also display shortened telomeres, damaged DNA, and the activation of specific genes, such as INK4 and ARF. In laboratories, scientists can identify senescent cells using a specific enzyme that “stains them blue”, making them easier to study.

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Senescence serves an important purpose in health. It is, at its core, a protective mechanism designed to safeguard the body and to accelerate healing. When cells become damaged or dysfunctional, senescence halts their division, preventing the proliferation of potentially harmful cells, such as those that could become cancerous. Afterwards, the immune cells clears them, stimulating tissue repair. In this way, senescence functions as a critical safeguard for the organism, ensuring that damaged cells do not threaten overall health.

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However, senescence also has a darker side. Judith Campisi’s research has revealed that when the immune system cannot effectively clear these senescent cells, they accumulate in tissues, where they start secreting inflammatory molecules. This condition, known as the Senescence-Associated Secretory Phenotype (SASP), creates a pro-inflammatory environment that, in turn, can turn other healthy cells senescent. While senescence initially acts as a protective mechanism, the buildup of these cells and the inflammation they cause can disrupt tissue health, accelerate aging, and contribute to a variety of age-related diseases. This chronic, low-grade inflammation, often referred to as inflammaging, is a major driver of aging and degenerative conditions.

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As we have discussed, research into cellular senescence is now focused on developing interventions that could mitigate its negative effects.

Preclinical studies are exploring the use of senolytic and senomorphic drugs:

·???????? Senolytics: Substances that aim to eliminate senescent cells.

·???????? Senomorphics: Drugs that modify the behavior of senescent cells without eliminating them by reducing their secretion of harmful substances.

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We will encounter these two terms (senolytic and senomorphic) many times, as several compounds are being developed in the field of longevity with these objectives.

In 2021, a team of Italian researchers led by Fabrizio d'Adda di Fagagna, from IFOM in Milan and IGM-CNR in Pavia, published a study in EMBO Reports that explores a new dimension of aging and its relationship to susceptibility to SARS-CoV-2, the virus responsible for the COVID-19 pandemic. The team found that telomere shortening and DNA damage, both of them mechanisms of aging, can increase the expression of angiotensin converting enzyme 2 (ACE2) in the lungs, which is the receptor used by the coronavirus to enter into the cells. This finding may explain why some people are more prone to suffer from severe symptoms from COVID-19. Once again, everything is connected!!!

In summary, cellular senescence is a fascinating yet complex hallmark of aging. While it begins as a beneficial process to prevent damaged cells from dividing, the accumulation of these cells and their inflammatory effects pose significant challenges to tissue health and longevity.

The 9th ?Hallmark of Aging is the exhaustion of stem cells, which are the body’s “repair system.” Stem cells are special cells that can divide and transform into various types of cells needed to regenerate and maintain our tissues.

As we age, the quantity and functionality of these stem cells decline. This means the body loses its ability to effectively repair damage, regenerate tissues, and respond to injuries or diseases. For example, fewer functioning stem cells can lead to slower wound healing, weaker muscle regeneration, and a reduced ability to replenish blood cells or immune cells. In addition to these changes, aging also changes the environment where these stem cells are located, which are called “niches”. Some niches, such as the stem cell niches located in the brain or in the bone marrow, become pro-inflammatory, triggering mechanisms of cellular senescence amongst stem cells.

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This decline in stem cell activity is a major contributor to the aging process, as it limits the body’s capacity to maintain and restore itself over time. I have explored already the role of Stem Cells in the 13 Issue, where we discovered that the role of stem cells has become a cornerstone in today’s longevity research.

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The 10th ?Hallmark of Aging is altered intercellular communication, which essentially summarizes and connects the effects of all the previous hallmarks. It highlights how aging impacts the way cells, tissues, and organs communicate with one another, leading to systemic dysfunctions.

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As cells accumulate damage over time—whether due to genomic instability, mitochondrial dysfunction, or telomere shortening—their ability to send and receive accurate signals becomes impaired. This hallmark is closely tied to chronic inflammation (Hallmark 11), often referred to as “inflammaging,” which is triggered by damaged cells that release harmful inflammatory molecules. We’ve already touched on chronic inflammation in Unlock Longevity Issue 4. This pro-inflammatory state disrupts communication between tissues and organs, contributing to aging on a systemic level.

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For instance, if a primary organ, such as the pancreas, loses its ability to produce essential hormones due to tissue degeneration, this will inevitably affect secondary organs and systems that depend on those hormones. Aging, therefore, is not just a localized process—it is deeply systemic.

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Interestingly, research shows that reversing damage in one area can have cascading benefits for other parts of the body. An example often cited—though ethically controversial—is parabiosis, an experiment in which the circulatory systems of two animals, one old and one young, are connected. This procedure has shown that the older animal can experience tissue rejuvenation due to factors in the younger animal’s blood, reinforcing the idea that aging is influenced by systemic signals.

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The last hallmark of aging, Dysbiosis, or microbial imbalance, highlights the critical role of the gut microbiome in systemic health and longevity. These new hallmarks reflect the evolving understanding of aging as a deeply interconnected process that involves not only our cells but also the ecosystems within us, or our hosts.

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I look forward to dedicating a future newsletter entirely to the microbiome—a fascinating and increasingly discussed topic in the field of longevity.

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So, I know these three newsletters have been a bit complex, but bravo for following along on this journey! Aging is a deeply intricate process, and together, we’ve explored the biological hallmarks that shape how we grow older.

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From genomic instability to telomere shortening, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis, we’ve touched on the key mechanisms driving aging and how they connect to longevity science.

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Understanding these hallmarks gives us a powerful foundation—not just to appreciate the science, but to make informed choices about health and longevity. There’s still so much to discover, and I’m excited to continue exploring it with you!

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.