Over a decade ago, five researchers published a paper proposing the Hallmarks of Aging paradigm: a set of cellular and molecular processes that underlie the aging process in different organisms. These hallmarks encompass a range of interconnected pathways, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient signaling, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Together, the hallmarks contribute to the gradual decline in physiological function and increased susceptibility to age-related diseases that occurs with age, and provide a framework for understanding how we age.

In this episode, Matt takes us through a quick download of each hallmark of aging, talks about some of the paradigm's shortcomings and limitations, and discusses the implications of the Hallmarks of Aging paradigm for the geroscience field.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The Hallmarks of Aging

This paper was the original “Hallmarks of Aging” paper that described nine common denominators of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The framework of “aging hallmarks”—that is, specific and identifiable molecular mechanisms or alterations that accompany the aging process—has provided a useful paradigm for understanding how certain biochemical changes form the essence of aging and of the disease and disability that accompanies it. However, we still don’t know a lot about the hierarchy of these hallmarks’ impact on the aging process or how they might interact with each other, and the evidence linking them to age-related disease is mostly correlative.

Hallmarks of aging: An expanding Universe

This paper proposes twelve hallmarks of aging and extends the work of the original 2013 paper outlining nine hallmarks of aging. The additional three hallmarks are disabled macroautophagy, chronic inflammation, and dysbiosis.

The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm

This paper is one of several sources offering a critique of the Hallmarks of Aging paradigm. It compares the hallmarks of aging to the hallmarks of cancer, the template from which the hallmarks of aging emerged. One of the papers criticisms includes that, unlike the clear causal chain in the hallmarks of cancer, the aging hallmarks' delineation of primary causes behind the aging process remains uncertain. The hallmarks of aging paradigm fails to elucidate how the hallmarks manifest as aging-related diseases. This disparity reflects, in part, a broader issue in geroscience concerning the definition of aging and its relationship with age-related diseases. The authors make suggestions for a new template encompassing various classes of primary mechanisms, including mechanical and molecular damage, infectious pathogens, and programmatic drivers of senescence.

Targeting the “hallmarks of aging” to slow aging and treat age-related disease: fact or fiction?

This paper offers another critique of the Hallmarks of Aging paradigm. The authors probe the evidence and assumptions upon which the paradigm stands—for example, that lifespan is a valid proxy for aging, or that certain animal models are appropriate for drawing inferences about aging. They conclude that the paradigm, along with other foundational geroscience concepts, may not actually hold water.

Do the Hallmarks of Aging Make SENS? (Part One)

This article compares two frameworks for understanding and addressing aging: the Hallmarks of Aging and the Strategies for Engineered Negligible Senescence (SENS) Seven (note that the SENS seven originated from the organization that published this article). It highlights that while the Hallmarks have gained widespread acceptance as a means to categorize aging-related changes, they focus on the metabolic processes contributing to aging rather than the damage itself. In contrast, the SENS approach targets the cellular and molecular damage directly, advocating for a "divide-and-conquer" strategy to repair or remove specific types of damage.