SIRT6 and Reversing DNA Changes in Aging

A new study in Nature Communications sheds light on a fundamental change in aging. The researchers showed that aging occurs in part due to DNA losing its organized structure inside cells. Importantly, they also showed that increasing a specific protein in that pathway could reverse some of the major age-related DNA changes.

Let’s dive into the details, and then look at some of the low-hanging fruit for modifying that pathway (without editing your genes :-).

What is chromatin? And why is it important in aging?

Your DNA is packaged up in specific ways to keep the genes that shouldn’t be translated into proteins hidden away - while leaving the genes that need to be accessed open for transcription. Chromatin is a package of both DNA and the histones that it is wrapped around, like thread on a spool. The chromatin can be loosely packed, allowing for easier DNA access for translating genes, or it can be tightly packed to prevent gene expression.

In aging, one of the problems is that chromatin is disrupted in ways that cause it to open up, allowing for translation of inflammatory cytokines at higher levels, while on the other hand, restricting some of the necessary metabolic pathways. Together, these changes lead to more inflammation and decreased cellular energy.

Essentially, the idea is that aging may be as much about disorganization in the genome, as much or more than, it is about accumulating damage in cells.

One way that genes are marked - turned on - for translation is through acetyl groups.

SIRT6 is an enzyme that deacetylates (takes the acetyl group off) chromatin. Researchers found that mice that lack SIRT6 have accelerated aging and end up dying young, at around 4 weeks of age. Prior studies also showed that overexpressing the SIRT6 enzyme results in extended lifespan and healthspan.

Why SIRT6 may help reverse aging:

The new study by Nagar et al.1 showed that not only is SIRT6 essential in maintaining the chromatin structure, but it also can be manipulated to reverse age-related changes.

The researchers looked at which genes were expressed differently in young mouse livers vs old mice. They then looked at what happens when they overexpress the SIRT6 gene.

In old mice, they found an increase in chromatin accessibility - it was opened up more than it should be. There was an increase in inflammatory gene expression and a downregulation of metabolic pathways.

When the researchers overexpressed SIRT6 later in life, through gene editing, they found that the age-related changes reverted to be more like those of young mice. In addition to downregulation of the inflammatory pathways, the lipid-storage and immune signals were restored to more youthful levels.

This is important because the changes were seen when applied at an old age (24 months) in mice. The researchers estimated that about 80% of the age-related changes were reversed by overexpression of SIRT6 late in life.

So how can we modulate SIRT6 levels without gene editing?

I’m not up for using CRISPR any time soon… so let’s take a look at more natural ways of modulating SIRT6.

Polyphenols from berries, especially cyanidin in red and purple fruits, can activate SIRT6.2 Eat your blueberries, blackberries, and raspberries this summer. You can also get cyanidin as a supplement (Amazon link as a reference, not necessarily a brand recommendation). The supplement contains the cyanidin equivalent of 6 pounds of blueberries.

Is eating blueberries going to turn back the clock for everyone? Yeah… probably not. But I like blueberries and am going to deliberately eat more organic blueberries. It will be huckleberry season here in Montana soon, so I’ll fight the bears for my share of huckleberries in July.

SIRT6 is dependent on NAD+, so maintaining NAD+ levels is one path to look at. Nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) supplements may help here.

Flavonoids, including quercetin and luteolin, can modulate SIRT6. Interestingly, quercetin can be an activator or inhibitor, depending on concentration. I’m not sure exactly how the dosing and absorption work out for quercetin concentration in humans, so luteolin may be a safer bet for activating SIRT6.3

Final thoughts:

I find it encouraging that the animal studies showed significant reversal of age-related chromatin changes, and I’m cautiously optimistic that this will translate into humans, at some level. However, I’m also cognizant of the fact that aging is multifaceted, with the likelihood that no single lever - no single intervention - is going to turn back the clock significantly. Each discovery, though, brings us a step closer to understanding the full picture of the mechanisms involved in aging.