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Suppose that your full-time job is to proofread machine-translated texts. The translation algorithm commits mistakes at a constant rate all day long; from this point of view, the quality of the translation stays the same. However, as a poor human proofreader, your ability to focus on this task will likely decline throughout the day; therefore, the number of missed errors, and therefore the number of translations that go out with mistakes, will likely go up with time, even though the machine doesn’t make any more errors at dusk than it did at dawn.

To an extent, this is pretty much what is going on with protein synthesis in your body.

Protein synthesis in a nutshell

The so-called coding regions of your DNA consist of genes that encode the necessary information to assemble the proteins that your cells use. As your DNA is, for all intents and purposes, the blueprint to build you, it is pretty important information, and as such, you want to keep it safe. That’s why DNA is contained in the double-layered membrane of the cell nucleus, where it is relatively safe from oxidative stress and other factors that might damage it. The protein-assembling machinery of the cell, ribosomes, are located outside the cell nucleus, and when a cell needs to build new proteins, what’s sent out to the assembly lines is not the blueprint itself, but rather a disposable mRNA (messenger RNA) copy of it that is read by the ribosomes, which will then build the corresponding protein. The process of making an mRNA copy of DNA is called “translation”, and as the initial analogy suggests, it is not error-free.

The spiral of doom

In the sixties, it was proposed [1] that the defective proteins resulting from these translation errors might, in the long run, further compromise the DNA-to-mRNA translation process in the cell, thus pushing up the rate of translation errors, resulting in even more defective proteins, and so on, giving rise to a downward spiral that could be one of the driving factors in aging.

This hypothesis (known as the “error catastrophe”) was eventually discarded, as further research didn’t show any significant increase in the rate of translation errors in aged cells and animals.

However, as discussed in a recent commentary [2], more recent studies discovered that mammalian cells in longer-lived species, such as the naked mole rat, make much fewer translation mistakes than do the cells in mice. From these studies, it would appear that a longer lifespan correlates with more accurate translation.

Loss of proteostasis

What is known—and this is where our analogy comes into play—is that whether or not the rate of translation errors goes up as we age, the rate at which the consequences of those errors are corrected goes down. Cellular mechanisms meant to break down and recycle unwanted proteins become less and less effective as organisms get older; this causes unwanted byproducts to pile up faster, even though the rate at which they are produced in the first place did not change at all.

This phenomenon, known as loss of proteostasis, is one of the hallmarks of aging, and it is characterized by a generalized decline of autophagy (the aforementioned cellular recycling skills). This may happen because lysosomes within cells have become clogged with unbreakable waste products that impair their functioning, thereby making them less able to degrade other waste products that they could normally digest without a problem. Another way this may happen is through the decline of proteasome activity, a slowdown in the action of large protein complexes that play a crucial role in the degradation of misfolded proteins outside the lysosomes.

This offers a plausible explanation for why longer-lived species have better translation mechanisms than others; if their recycling mechanisms go downhill just like anyone else’s with time, causing subsequent damage to be repaired increasingly less efficiently, you wouldn’t expect them to live much longer unless they had to deal with less damage in the first place—for example, by having more accurate protein translation.

What about us?

A variety of age-related diseases, including Parkinson’s and Alzheimer’s, have protein aggregation among their causes. If we want to get rid of these diseases, this problem needs to be solved in one way or another. Slowing down the rate at which misfolded proteins are churned out might require tinkering with mechanisms that we don’t fully understand and that could easily wreak havoc in our bodies if disturbed, which is a less preferable option than upgrading our cells’ ability to recycle broken proteins, such as by equipping lysosomes with new enzymes that can break down hard-to-digest garbage.

Literature

[1] Orgel, L. E. (1963). The maintenance of the accuracy of protein synthesis and its relevance to ageing. Proceedings of the National Academy of Sciences, 49(4), 517-521.

[2] Ke, Z., Seluanov, A., & Gorbunova, V. (2018). Accurate translation is important for longevity. Aging.

CategoryNews, Research
About the author

Nicola Bagalà

Nicola is a bit of a jack of all trades—a holder of an M.Sc. in mathematics; an amateur programmer; a hobbyist at novel writing, piano and art; and, of course, a passionate life extensionist. After his interest in the science of undoing aging arose in 2011, he gradually shifted from quiet supporter to active advocate in 2015, first launching his advocacy blog Rejuvenaction before eventually joining LEAF. These years in the field sparked an interest in molecular biology, which he actively studies. Other subjects he loves to discuss to no end are cosmology, artificial intelligence, and many others—far too many for a currently normal lifespan, which is one of the reasons he’s into life extension.
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