miRNA Regulation and Aging: The Epigenetic Levers of Lifespan
How miRNAs change gene expression and cause the changes seen as we age.
Why do our muscles weaken, our metabolism slow, and our immune system falter with age? Tiny bits of RNA encoded in our genome, called microRNAs, play a big role in the changes we experience as we get older.
MicroRNAs control gene expression, and changes in miRNAs are a driving force in aging. Let’s dig into the details here and see how and why this happens.
Background on gene expression and epigenetics:
Your genes are the same in every cell, but a liver cell doesn't look or act like a brain cell. Similarly, a skin cell in a young person is not exactly the same as an old skin cell.
Epigenetics is a term that people use in different ways, but it is generally used to describe the heritable markers that control gene expression, as well as changes in gene expression that occur throughout life, often in response to environmental factors.
Researchers are working on being able to revert cells back to a younger phenotype by altering epigenetic marks. It’s interesting research, and I hope that it works (without increasing cancer).
Epigenetic marks, such as methyl groups, can prevent a gene from being transcribed.
To set the stage, here’s what is called the central dogma of biology:
gene —> transcribed to mRNA —> translated to protein
Epigenetic marks can prevent (or allow) a gene from being transcribed. There are also multiple mechanisms to change gene expression after transcription.
One way to prevent a gene that has been transcribed into mRNA from being translated into protein is for microRNAs to attach to the mRNA, preventing translation. I think of them like a dimmer switch that is able to turn up or down the expression of a protein.
That’s where I want to focus today: miRNAs that are altered in aging and cause the decline seen in aging.
I do think that epigenetic reprogramming of cells to turn them back to a young cell may be possible at some point — but it isn’t something that is realistically going to happen very soon or in an easily accessible way. So instead, I’m going to focus on the more realistic ways that we can alter gene expression to turn back the clock just a bit.
MicroRNAs that are altered in aging:
There are more than 1,000 known human miRNAs. Each of these short strings of RNA can attach to multiple mRNAs and affect the gene expression of 100+ genes, in some cases.
Man of the initial studies on miRNAs narrowly focused on specific genes in cell lines or animals. However, since changing miRNA levels can affect different systems throughout the body, there can be unwanted side effects from manipulating gene expression this way. Keep this in mind as you read miRNA research studies, including the studies below. There are likely still unknowns…
MiR-34a, NAD, and mitochondrial function:
NAD levels decline in aging, and supplementing with NR or NMN can help to combat the decline. (Read more on NR and NMN supplements for aging here.) [ref]
MiR-34a is a microRNA that increases with aging (and with obesity).[ref]
Increased miR-34a is associated with:
decreased SIRT1 expression (and subsequently, increased cellular senescence)[ref]
decreased NAMPT and NAD+[ref]
liver fibrosis[ref]
neurodegenerative diseases[ref]
Decreased miR-34a is associated with increased proliferation in certain types of cancer.[ref]
Ways to suppress miR-34a:
Possible ways to suppress the upregulation of miR-34a in aging (assuming you don’t have cancer…):
pterostilbene[ref] (available as a supplement or combined with NR for an added benefit on this pathway)*
urolithin A[ref] (available as a supplement)
resveratrol[ref] (available as a supplement in powdered form, minimal taste)
MiR-29 as a driver of aging through senescence and fibrosis:
A 2024 study in animals clearly shows that miR-29 expression is important in aging. In a mouse model of accelerated aging, decreasing miR-29 can extend lifespan. The researchers also showed that increasing miR-29 accelerates aging and death.[ref] Other research shows that miR-29 promotes senescence by upregulating p53.[ref]
Studies show that miR-29 increases in aging, and overexpression of miR-29a in muscle causes decreased collagen levels and increased fibrosis in the heart.[ref]
Calorie restriction downregulates miR-29, which may be one reason that calorie restriction extends lifespan.[ref] A methionine-restricted diet also downregulates miR-29.[ref]
Ways to target miR-29:
Intermittent fasting may be a good way to target miR-29.
Alternatively, a periodic day or two of of methionine restriction (essentially a very low protein diet) would be another way to decrease miR-29. This is just speculation on my part.
MiR-181a control mitochondria function and skeletal muscles in aging:
Researchers have identified MiR-181a as a key regulator of the decline in muscle function in aging. MiR-181a controls the gene expression of multiple genes involved in mitochondrial function that are particularly important in skeletal muscles (HOXA11, SIRT1, PTEN, and PARK2).
In aging, miR-181a levels decrease, and counteracting that decrease helps mitochondria to function more efficiently, preventing age-related muscle loss.[ref]
MiR-181a also has important roles in the immune response in aging, affecting both T cells and natural killer cells.
Lower levels of miR-181a also play a role in the decline and changes seen in T cell function in aging. This negatively affects the ability of older individuals to clear a viral infection.[ref]
Lower levels of miR-181a in aging also cause a decrease in natural killer cell function and subsequently decrease interferon-gamma. Again, this is part of the decline in the ability to fight off viral infections in aging.[ref]
(You may be thinking that a miRNA that affects skeletal muscle energy and immune response could be implicated in ME/CFS. MiR-181a is one that has been identified as being differentially expressed in chronic fatigue.[ref])
In cancer, miR-181a has opposite effects, depending on the type of cancer. For example, in colon cancer, miR-181a increases proliferation through regulating PTEN. In other types of cancer, higher levels of miR-181a can be a positive factor by preventing metastasis.[ref]
Ways to increase miR-181a:
Calcitriol, the active form of vitamin D, increases miR-181a.[ref]
This is the vitamin D that I use during the winter months. I picked it because it includes coconut oil in the softgel. So many vitamin D supplements seem to include types of oil that I don’t want, such as cottonseed or soybean.MiR-181a levels are also decreased in obesity.[ref] Thus, weight loss may naturally increase miR-181a.
MiR-188 and the middle age spread:
Mir-188 expression increases in aging and is associated with the aging metabolic phenotype, which is a fancy way of saying decreased energy and increased weight.
Bone marrow mesenchymal stem cells can differentiate to form adipose (fat) cells or osteogenic cells. In aging, a shift takes place where we form more fat and less bone (osteoporosis), resulting in a middle-aged spread with weaker bones. MiR-188 is a key to this shift.
The increased miR-188 in aging mice causes bone loss and higher adipose production in bone marrow. [ref] Researchers have also found that miR-188 increases in adipose tissue (more fat) during aging. They created a mouse model with miR-188 knocked out and found that there were no differences during the first half of life. In the normal mice, energy metabolism went downhill starting in mid-life along with the increase in fat. The miR-188 knockout mice, on the other hand, ate the same amount of chow but didn’t have a decrease in energy metabolism nor an increase in weight. The researchers went on to experiment with inhibiting miR-188 in aging mice and found that the miR-188 inhibitor could reverse the aging metabolic phenotype. [ref]
MiR-188 in humans:
Ok, so miR-188 inhibition is a great way to keep mice from having the middle-aged spread and decline in energy. But what about in humans? MiR-188 affects the gene expression in several ways - more than just bone and fat:
Increasing miR-188 inhibits cell proliferation in cell studies, showing that it may act as a tumor suppressor in specific types of tumors.[ref] For example, miR-188 is downregulated in lung cancer patients.[ref]
MiR-188 is decreased in neurons in Alzheimer’s disease. Importantly, restoring miR-188 rescues synaptic function.[ref]
In men with azoospermia, miR-188 expression is downregulated, which plays a role in sperm cell death.[ref]
Ways to inhibit miR-188:
So…. messing with miR-188 levels could affect cancer proliferation, sperm formation, or Alzheimer’s risk. Perhaps we should just put up with the middle-aged spread.
On that happy note, I’m going to bring this to a close.
Conclusion:
While researchers are still piecing together why and how miRNA levels shift with age, what’s clear is that they are key to understanding — and perhaps slowing — the aging process.
Researchers are actively looking at ways of increasing or decreasing miRNA levels; with the small size and polarity of the molecule, they can easily be synthesized and injected into the body. However, with so many different genes as targets, an miRNA injection may have a lot of off target effects.
While I don’t have a lot of solutions to offer here, I hope this article has illustrated the complexity of the body as a system with multiple controls on gene expression that function systemically instead of just in a single tissue.
Questions that remain (for me):
While miRNA controlling gene expression explains much of what goes on in aging, I don’t know why the miRNA levels change from young to old. What is the overarching control here? There’s still a lot more that I need to learn on this topic.