CU Boulder researcher Jesse Kurland shows in new study that aging is a complex process affecting genetic networks, and altering one gene won’t stop it

As anyone who’s ever said “oof” while sitting down knows, the effects of aging are felt across every tissue and every organ in the body.

One of the tissues most affected by aging is skeletal muscle, which allows us to breathe, eat and move ourselves through the world. As we age, skeletal muscle tissue becomes smaller, weaker and less capable of regenerating itself after injury—leading not only to physical decline, but also mental decline.

And despite what humanity has hoped for since long before Ponce de Leon sought the Fountain of Youth, and especially since researchers began scouring the human genome for a genetic silver bullet that might arrest or even reverse the process of aging, the news isn’t promising: A single, miraculous genetic cure probably doesn’t exist.

Newly published research focusing on skeletal muscle tissue highlights how, rather than being driven by the expression of one gene or even small clusters of genes, the aging process disrupts the timing of expression in entire gene networks. 

“This research makes me a little skeptical that one day we will have the means to reverse aging,” says University of Colorado Boulder researcher Jesse Kurland, the study’s lead author who earned his PhD in molecular and computational biology in June by defending this research. 

“Though there are methods, like diet and exercise, that appear to temporarily slow the aging process and increase lifespan, for decades researchers studying the genetics of aging have searched for a ‘magic bullet’ to actually halt or reverse aging, and I’m doubtful of that ever succeeding. 

“It’s hard to imagine how a process that disrupts our tissues universally in such complex ways, and in fundamental cellular processes like transcription (the process in which information in a strand of DNA is copied into a new molecule of messenger RNA), could be fixed by altering one, or even handfuls, of genes.”  

Complexities of aging

Kurland and his colleagues focused on skeletal muscle tissue not only because it’s critical to overall human health and well-being, but because the factors driving its age-related decline in function and ability to regenerate itself are not well understood. 

Skeletal muscle is one of a few tissues that contain stem cells in adulthood, which are critical for their function and maintenance. In muscle, a population of resident quiescent stem cells (MuSCs) activate and proliferate to regenerate muscle tissue after injuries. Failure to maintain and repair skeletal muscle in aged organisms is attributed, in part, to deficits in MuSC function, but the full picture of why muscle regeneration declines in aging remains unclear.

During muscle regeneration, gene expression—when information in DNA is converted to a functional product like protein—must be turned on and off in coordinated sequences to transform muscle stem cells into mature muscle cells, a process known as cell differentiation. 

In muscle regeneration, sets of related genes, referred to as gene networks, are turned on during cell differentiation and subsequently regulate expression of other gene networks. This process keeps happening in a tightly coordinated cascade of gene-expression changes. 

Kurland and his colleagues combined mouse experiments with advanced computational analyses in a multidisciplinary approach and made several significant observations. They saw that during muscle regeneration, miscoordination of gene-network expression is what primarily distinguishes regeneration in aged mice from young mice. Their observations support the idea that this miscoordination actually “snowballs” during regeneration, during which disruptions increase in magnitude and severity as regeneration proceeds.

Many researchers have argued that muscle regenerative declines in aged organisms are due to overall changes in gene expression, suggesting that aging inhibits expression of genes normally turned on in young organisms during regeneration, and activates genes that should be turned off. 

However, Kurland’s research challenges this notion by arguing that changes to the timing of gene expression, rather than a binary, on-or-off sequence of particular genes, is the primary contributor to defects in muscle regeneration and function in aging organisms, “which is a subtle but profound difference of perspective,” Kurland notes. 

His research suggests that aging may broadly result from miscoordination of large groups of interconnected genes, thus making it unlikely that turning single genes from these networks on or off would halt or reverse aging. In other words, aging may be a case of right gene, wrong time.

What is aging?

Kurland notes that “we barely have a grasp on what aging even is. Some theories suggest it’s an evolutionarily conserved process to limit population size. There’s also an entropic theory of aging, which expresses that the order inherent in all life can only be temporary and must eventually return to disorder. Ultimately, it seems aging is somehow related to the very nature of time, which, when you get down to it, is also an utter mystery.

“For me, one of the most fundamentally baffling questions about aging is why some animals, like our cats and dogs, only live 10 to 20 years, while some whale species live hundreds of years. There are even species of jellyfish that can reverse aging by mechanisms we don’t understand. I don’t know if we’ll ever fully understand why we age, so in a sense I wanted to portray ways in which aging is a lot more complicated than we’re even beginning to grasp.”

He advises that “all aging research and proposed lifestyle changes should be taken with a grain of salt, and instead we should ask ourselves ‘How do I feel compared to how I felt a year ago? Is my lifestyle working well for me?’

“Personally, I have no interest in reversing my own aging or living forever. Aging is a fundamental and natural part of life—for organisms to be born, others must die. We should all try to embrace the aging process rather than avoid it. We shouldn’t let our desire to remain youthful get in the way of enjoying all phases of our lives.” 

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