Extending lifespan with miRNAs

microRNAs to the rescue?

MicroRNAs are short segments of RNA that can bind to mRNA and prevent the mRNA from being transcribed into its protein

These miRNAs can essentially fine-tune gene expression. If there's more of a particular miRNA available in the cell, the amount of protein expressed in the gene will decrease. Similarly, if there is less of the miRNA, it can increase gene expression.

MicroRNAs are an important regulatory mechanism for all aspects of cellular function - including cellular senescence.

(I just wrote about miRNA on Genetic Lifehacks — check it out if you want a really quick refresher on DNA, gene transcription, and mRNA translation into a protein.)

A new study on miRNA targeting and reversing cellular senescence:

A new study (in mice) shows that microRNAs can be used to stop excessive cellular senescence and extend lifespan.

Cellular senescence is the state in which a cell is no longer able to replicate and it sends out inflammatory signals so that the immune system comes and removes it. This happens all the time throughout life, but as we age, the number of senescent cells can exceed the ability of the immune system to quickly remove them. The accumulation of senescent cells, which give off inflammatory signals, then increases the overall inflammation of aging - negatively affecting nearby cells, and everything goes downhill.

MicroRNAs are cool because they are small (22 nucleotide bases) and can be packaged in extracellular vesicles. These packaged EVs with miRNA can be absorbed through the intestines — and thus could be used as drugs.

Rabbit trail: We actually absorb miRNAs from some foods, such as cow’s milk and eggs, and these miRNA extracellular vesicles can circulate.

The researchers figured out that a specific miRNA, called miR-302b interacts with the cell cycle inhibitors Cdkn1a and Ccng2. Blocking these cell cycle inhibitors reversed cellular senescence. By inhibiting Cdkn1a and Ccng2 with miR-302b, the senescent cells could resume cell division.

The researchers then gave miR-302b to mice at middle age (20 months) to see the effect. The mice that received the miR-302b EVs lived an average of four months longer (38 months vs 34 months). They also regrew hair, maintained their weight, and were healthy and stronger for longer — increased healthspan. Pretty cool!

Surprisingly (to me), the 12% increase in healthspan and lifespan didn’t come with any noted adverse effects.

The catch is that cellular senescence is one of the ways the body prevents tumors and cancer - it stops out-of-control growth. So it surprised me that you could target a cell cycle inhibitor and not increase cancer.

The other thing to know is that each miRNA acts on and regulates the expression of multiple genes, so altering miRNA levels can often have off-target effects.

So what is miR-302b?

Let's look at some human studies on the multiple functions of miR-302b:

In cancer cells, increasing miR-302b may be good:

• A study in mice and cell lines found that miR-302b degrades DKK1, which then suppresses cell proliferation and increases apoptosis. In multiple myeloma, increasing miR-302b stops the destruction of bone. [ref]

• In glioma (brain tumor) cells, increasing miR-302b can kill the cancer cells. The study showed that miR-302b overexpression downregulated 150 genes and upregulated 380 genes.[ref]

• In melanoma cells, miR-302b levels are low. Adding a synthetic miR-302b mimic increased the melanoma cancer cell death.[ref]

In gout (or in cells treated with urate crystals), miR-302b levels are really high, and the overexpression of miR-302b regulates NF-κB, leading to lower inflammatory cytokine (IL-1β) levels.[ref]

The flip side is the response to viruses:

• MiR-302b is also involved in mitochondrial function in response to viral infection. One study showed that inhibiting miR-302b increased SLC25A12, which is a mitochondrial protein involved in the response to RNA viruses. The results showed that miR-302b is important to have at the right level to allow the virus to be targeted but without an excessive immune response.[ref]

• In Covid, miR-302b levels are downregulated in both asymptomatic and symptomatic infections compared to healthy controls.[ref]

What influences miR-302b expression?

In addition to viral infections and a response to cellular stressors (like urate crystals in the gout example), researchers have found that exogenous substances can affect miR-302b expression.

• Estrogen (E2) given as17-estradiol nanoparticles downregulates miR-302b in rats with heart attacks.[ref]

• Mercury increases miR-302b expression.[ref]

To sum up, 500+ genes can be influenced by miR-302b. Cells make miR-302b to fine-tune gene expression with the cell, but miRNAs can also be exported from the cells and taken into other cells via extracellular vesicles.

Conclusion:

About 150,000 papers on miRNA have been published in the last decade. It’s a hot topic, and the ability to control gene expression with a small RNA molecule wrapped up in a lipid nanoparticle is tantalizing (and lucrative?). In cancer research, iron nanoparticles combined with miR-302b could be targeted to a tumor using a magnet.[ref]

However, there's still a whole lot of research to be done before miR-302b extracellular vesicles can be used to treat cellular aging in humans. The odds of an off-target response in some people, such as mitochondrial dysfunction due to a persistent viral infection, are significant. But the fact that nothing negative was seen in the mice is quite intriguing.

To add a little more complexity, the ability of a particular miRNA to stop an mRNA from being translated into its protein can be altered by SNPs in the gene encoding the protein. Thus, miRNAs as a drug may cause slightly different off-target responses depending on the individual’s genetic variants.

More to come:

I’m going to write more in the future about how miRNAs affect gene expression — and how exposure to BPA and microplastics interacts with different miRNAs. Plus, there’s some cool research on how miRNA extracellular vesicles in foods, such as milk or eggs, are taken into the body and can affect our health.[ref - this one is cool]