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The Hallmarks of Aging: A Guide to the Pathways of Aging

You may have heard longevity experts speak about the 'Hallmarks of Aging' but did you know that by inhibiting them, we can actually slow the pace at which we age? Let's take a closer look at what these signs of aging are and how to counter them. Knowledge is power, right? 

The Hallmarks of Aging: What's the Criteria?

The nine hallmarks of aging were first put forward in a paper published in the journal Cell in 2013 by Spanish scientist Carlos Lopez-Otin and his colleagues. To be considered a hallmark, Lopez-Otin stated that a biological process must fulfill (to varying the degrees) the following three criteria: 

  1. It should manifest or happen during normal aging
  2. Experimental acceleration or increase of the hallmark accelerates normal aging
  3. Experimental reduction of the hallmark slows normal aging 

The third criterion is obviously the most exciting—reduce or stop a hallmark and increase healthy lifespan. That’s certainly a pill most people would buy. But it’s also the most difficult to achieve or prove in the lab. Lopez-Otin and team explain this, particularly for the hallmarks for which this criterion is not fulfilled, by citing their “extensive interconnectedness.”  That means that the hallmarks work in combination to cause aging.

The cause of aging

It could be helpful at this point to broadly define the cause of aging, or at least how many scientists see it coming about. Aging is caused by “the time-dependent accumulation of cellular damage.” This means, as we age, damage in the cells accumulates and the cell’s ability to function declines; this reduction in function—sometimes called a loss of integrity—is the primary risk factor for many diseases including, and this is just a sample, cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases and death.  

The aging car (cell)

Let’s think of a cell as a shiny new car. At first, most cars function perfectly. But, regular maintenance is required—keeping it clean and replacing parts (autophagy) and addressing computer glitches (DNA repair), for example. But, with wear and tear, even despite this maintenance, parts may fail (loss of integrity). If they aren’t repaired or replaced, for whatever reason, the damage spreads to other parts. Then, the car breaks down—blowing a gasket (heart attack, if you will)—and the mechanic suggests that the damage is irreparable. You may send it to the junkyard (cell death).  To a degree, though oversimplified, this is what happens to cells as they age.  

So, what is causing the damage? 

Wine. I am just kidding, but a brief released this year by the World Heart Federation suggests that any level of drinking can lead to loss of healthy life. Cry with me. 

The hallmarks are broken down into three groups: primary, antagonistic, and integrative. In this blog series, we will explore each hallmark in turn. But for this, the introduction, we will briefly introduce the groups and the hallmarks.

The Primary Hallmarks of Aging

The primary group is so named because they are the primary causes of cellular damage. According to Lopez-Otin and team, the common characteristic of the primary hallmarks is the fact that they are all, unequivocally, negative.  

For example, the first hallmark, genomic instability, which we’ll explore in more depth in the next blog, essentially means accumulated DNA damage to a destabilizing degree.  To follow the analogy above, a simple comparison might be glitches in the car’s computer to the point where it is either nonfunctional or tells you that you are in Bristol, when you are, in fact, in Bath. You don’t want this to happen to your cells’ DNA or your car’s computer. 

Included in this group are the following:

  1. Genomic instability -BAD
  2. Telomere shortening -BAD
  3. Epigenetic alterations -BAD
  4. Loss of proteostasis -BAD

The Antagonistic Hallmarks of Aging

The antagonistic group are so named because they are responses to the primary hallmarks. In contrast to the primary hallmarks, antagonistic hallmarks have opposite effects depending on their intensity. At first, at low levels, these responses mitigate the damage caused by the primary hallmarks, but eventually they become harmful themselves. For example, the seventh hallmark senescence, or cell cycle arrest, can protect the organism from cancer (uncontrolled cell cycles); but, in excess, can promote aging.

Included in this group are the following:

  1. Deregulated nutrient sensing – Sometimes bad
  2. Mitochondrial dysfunction – Sometimes bad
  3. Cellular senescence – Sometimes bad 

They can be viewed as being designed for protecting the organism from damage or nutrient scarcity, but “when exacerbated or chronic, they subvert their purpose and generate further damage.”

The Integrative Hallmarks of Aging

The integrative hallmarks arise when the accumulated damage caused by the primary and antagonistic hallmarks cannot be compensated by the cell’s mechanisms to promote homeostasis; this includes reparative processes, for example, comparable to the regular maintenance offered by the mechanic in the example above. 

Integrative hallmarks lead to further deterioration of cells that are ultimately responsible for aging. Both of the following directly affect tissue homeostasis and function: 

  1. Stem cell exhaustion – This is the end 
  2. Altered intercellular communication - This is the end

Why the “Hallmarks of Aging”?

This paper inspired thousands of later studies on the molecular mechanisms of aging and promoted intervention, through mitigation of the hallmarks, that promote the human healthspan. We are still talking about it nearly ten years later and the number of studies and papers continues to rise. It doesn’t mean that one day, as we understand more, that a hallmark may drop out (think Pluto) or that one hallmark might prove to be the crux of it all, but it is a good framework, for scientists and aging bloggers alike, to explore what we know, how we know it, and how we might live better for longer.

Written by: Katsume Stoneham, BS, Molecular Biology, MA, Public Health

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