Slower Protein Turnover in the Aged Brain

Metabolic activity slows down in late life, perhaps in large part because this reduces the risk of cancer. In an environment of pervasive molecular damage, a growing burden of nuclear DNA mutations, inflammation, and a declining immune system, more cellular replication and activity implies an ever greater risk of cancer. Longevity in our species appears to be a trade-off that selects for a slow decline in tissue function coupled to a lower cancer risk, rather than maintained tissue function coupled to a higher cancer risk.

Greater human longevity relative to other primates is a comparatively recent development in evolutionary history, likely the result of our greater intelligence and capacity for culture. When older people can significantly influence the reproductive success of their grandchildren, there is a selection pressure for longer lives. This view of exceptional human longevity is called the grandmother hypothesis, and may also explain some other aspects of human physiology and aging that are unusual among mammals, such as the existence of menopause.

We should expect to see signs of slowed metabolic activity wherever we look in human cellular biochemistry and cell behavior. For example, stem cell activity declines in response to the aged tissue environment; fewer daughter somatic cells are generated to replace those that should turn over. Cell division rates decline in general, and cells spend longer in their tissue before reaching the Hayflick limit. As today's open access paper notes, the synthesis and turnover of proteins in cells may also exhibit a slowdown in at least some cell types. These slowdowns have consequences. We can consider that cells and proteins are likely to accumulate more stochastic damage and exhibit more dysfunction in many ways, for example, given longer working lifetimes.

Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration

Analysis of brain protein levels in physiologically aged brain has revealed only minor alterations in protein abundances in the aged adult versus the young adult brain, reflecting differences in inflammation-related proteins or changes in proteasome and ribosome stoichiometry. This indicates that protein turnover, which regulates the equilibrium between protein synthesis and degradation, might be especially affected in aging and could lead to changes preluding neuropathology. Protein synthesis has been historically described as declining with age, although not all studies agree and often point to high organ and tissue variability. Protein degradation is also commonly described as compromised in aging. If both synthesis and degradation decline, lifetimes should increase and general turnover of proteins should be slower, possibly favoring the collapse of proteostasis networks and initiating the accumulation of potentially toxic proteins. While this general trend would explain the malfunctioning of macromolecules, protein turnover in different tissues has shown little or no overall changes in aged animals versus younger controls.

While results in invertebrate models suggest that proteostasis is essential for the survival of aging neurons, and that there is an age-related decline in protein turnover rates, in the aged mammalian brain an extensive quantitative analysis of protein turnover is currently lacking. Our group has introduced an experimental workflow for the global quantification of protein lifetimes. Here, using this workflow, we obtained protein lifetimes in the aged brain cortex, in cerebellum, and in their synaptic fractions, aiming to provide cellular and subcellular information about changes in brain protein stability. We then compared protein lifetimes between young adult and aged mice addressing the changes observed during aging. We analyzed our results extensively with bioinformatics and revealed that the proteome in the aged brain is turned over at a slower rate (~20%). In addition, aging establishes an intrinsic alteration of the proteostasis network that specifically preserves proteins with high biosynthetic cost.


Off topic, but I saw this news today that apparently your liver stays around 3 years old your entire life:

""By comparing the values to the levels of atmospheric radiocarbon, we can retrospectively establish the age of the cells."

To put the idea into practice, the team analyzed the radiocarbon levels of the livers of 33 deceased people between the ages of 20 and 84 years. And sure enough, they found that the organ was roughly the same age - a little under three years old on average - no matter the age of the person. But not all cells in a given liver were the same age - some were found to regenerate every year or so, while others could stick around for as long as a decade. Intriguingly, the longer-living cells were those that had accumulated more sets of chromosomes."

Posted by: jimofoz at June 4th, 2022 6:57 AM

I am not convinced by this hypothesis (the article). An impaired tissue function will wash the lineage out of the gene pool sooner than the higher risk of cancer in later life. The reduced functionality affects not only the proverbial running away from tiger but also the immune system, ability to work/forage for food and the ability to avoid and survive accidents. It is plausible that more metabolically active immune system might even lead to reduced cancer incidence.

As for comparison against other apes, we don't be really have many days points. The chimps seem to have somewhat shorter health and life span than humans but since we have so much more humans they chimps living in captivity, where we can record and observe their aging we might have a selection bias. On top the chimps in captivity might not be in the healthiest environment . Taking all this into account , especially The fact that they are quite a different species than ours some 30 -50% of a difference are to be expected, we are surprisingly similar and have similar aging patterns and lifespan.

Many "primitive" or rather traditional cultures srull have the first adulthood rites of passage around 13 years old. This reflects how brutal life the first homo members had, where it was necessary to procreate say that age. And now we, arguably, consider 25-27 to be there prime of the phonecall shape. That's like a whole"generation" . 13 more and we go to 40 which is the end of being "young". The "midage" and the beginning of malaise. And with enough luck we can go on till 65 without major issues.
That's our biological legacy. It body happens that the social roles and increased educational expectations shift the generation to low 20s. And if we consider careers and even to 30.

Posted by: Cuberat at June 4th, 2022 3:56 PM
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