I know it when I see it.

So how do we know what actually constitutes longevity?

I’ve had a lot of conversations about longevity and they almost always arrive at some form of this question.

Frameworks are essential not only for understanding a topic or space but also being able to operate in one. If you’re an investor thinking of putting money into longevity companies or a consumer trying to understand what’s available, a framework can help you make sense of the daunting amount of rapidly evolving information.

Longevity has two major frameworks: the Hallmarks of Aging and the SENS theory. They are both highly technical, existing at the organismal, cellular, and sub-cellular levels.

For each of these frameworks, over two separate posts, I’ll cover the following:

• A very brief history of how the framework came to be

• The components of the framework, explaining what each means in non-technical terms

• How each component alters our approach to medicine

An important point: many of the components of these frameworks correlate to increased lifespan but have not yet been shown to cause increased lifespan.

For components without direct causal links, a therapeutic target may not necessarily have a desirable impact. In some cases, the impact can even be negative. I will point out when a specific treatment, indication, or linkage is causal. I won’t go into treatment options for those that aren’t since there’s limited evidence that any reduction in variable x would affect aging given it’s not provable that x has any affect on aging.

For now, I’ll restrict all discussion to therapeutics and save debate on diagnostics, supplements, and lifestyle changes for another time.

The Hallmarks of Aging

The original Hallmarks of Aging paper, published in 2013, laid out 9 “hallmarks” of aged cells. The latest version, published in January 2023, modifies the framework to bring the total to 12.

Primary

The hallmarks are divided into 3 subcategories. The first, “primary” hallmarks, are the primitives of aging. They form the compositional units of the aging process.

Genomic Instability

Think back to when you were in school and you got a worksheet that was photocopied from a photocopy at least a dozen times over, getting fuzzier and blotchier until eventually it looked like it was written by a drunk pirate. You could say it didn’t age well.

Genomic instability progresses in the same way; aging involves the accumulation of genetic damage throughout life. Exogenous events such as exposure to sunlight (specifically, UV rays) leads to permutations in DNA. Organisms have evolved DNA repair mechanisms to counteract damage and maintain genomic stability, which is why a key part of this hallmark is the breakdown of these very systems. The accumulated defects in repair systems and the genetic code itself leads to cells which do not function as intended.

Telomere Attrition