FOXO1 Influences Proteosomal Function via Regulation of the Expression of a Proteasome Subunit

The proteasome is a complex structure in the cell that is responsible for breaking down unwanted proteins. Like other recycling processes, proteasomal function is connected to life span in short-lived species. Better cell maintenance in response to stress and damage improves cell function, organ function, and longevity. The proteasome is made up of many different proteins, produced in the cell at difference rates. The least produced proteins are rate-limiting for proteasomal activity, and researchers have shown that boosting production of some of the proteasome subunit proteins can improve proteasomal function and increase life span in flies and nematodes. In the work here, researchers suggest that the transcription factor FOXO1, known to influence life span, works at least in part through this mechanism: it may either influence proteasomal function by determining the number of subunit protein molecules that are available for use in the cell.

Proteostasis collapses during aging resulting, among other things, in the accumulation of damaged and aggregated proteins. The proteasome is the main cellular proteolytic system and plays a fundamental role in the maintenance of protein homeostasis. Our previous work has demonstrated that senescence and aging are related to a decline in proteasome content and activities, while its activation extends lifespan in vitro and in vivo in various species. In addition, pharmacological or genetic induction of the proteasome alleviates the pathological phenotype of protein aggregation-related diseases, such as Alzheimer's disease. Here, we demonstrate that the Forkhead box-O1 (FoxO1) transcription factor directly regulates the expression of the 20S proteasome catalytic subunit β5 and, hence, proteasome activity.

The 20S core proteasome has barrel-like configuration and is comprised by seven different α subunits and seven distinct β subunits. Three β subunits, namely β1, β2, and β5, possess proteolytic activities with different substrate specificities. We have shown that human mesenchymal stem cells (hMSCs) exhibit a senescence-related decline of proteasome content and aberrations in physiological assembly of proteasome complexes during prolonged in vitro expansion, while proteasome activation via overexpression of the catalytic β5 subunit can enhance their stemness and lifespan.

We demonstrate that knockout of FoxO1, but not of FoxO3, in mice severely impairs proteasome activity in several tissues, while depletion of IRS1 enhances proteasome function. Importantly, we show that FoxO1 directly binds on the promoter region of the rate-limiting catalytic β5 proteasome subunit to regulate its expression. In summary, this study reveals the direct role of FoxO factors in the regulation of proteasome function and provides new insight into how FoxOs affect proteostasis and, in turn, longevity.



Hey, just thanking you for taking so much of yout time to answer my comment into the last post.

Just answering somethings I think, I will study and do my best to age the slowest possible. I'm 20yo starting medical school. Maybe naturally I can't be immortal but I can at least try to live more 90 years ultil we have reversing aging therapies.
As you said into some of your posts, it's better to try to reverse aging than slowing it. I don't belive any drugs can slow aging. Any drugs we take can heal something but will aways cause others damage as collateral, it may be little, but taking medication for decades can become a lot. So I intend to slow my aging naturally ultil we have true reverse aging therapies.
I want to know your opinion about an article I read. I was researching about hayflick limit and I read an article of "The conversation":

"The Hayflick limit may represent an organism's maximal lifespan, but what is it that actually kills us in the end? To test the Hayflick limit's ability to predict our mortality we can take cell samples from young and old people and grow them in the lab. If the Hayflick limit is the culprit, a 60-year-old person's cells should divide far fewer times than a 20-year-old's cells.

But this experiment fails time after time. The 60-year-old's skin cells still divide approximately 50 times - just as many as the young person's cells. But what about the telomeres: aren't they the inbuilt biological clock? Well, it's complicated."

Why do you think that happened?
Another thing is that you focus a lot into "healing/ reverse aging" of cells. Why not try to replace them for younger cells? Implanting stem cells and stimulating older cells to "auto destroy" by autophagy or the immune system. Of course the stem cells would have to have our DNA and would take decades to have this biotechnology.
I wanted to know how to take care of our gametes too because something that worries me in today's society is that we are having children too old. Our grandparents had children in theirs early 20s and now we are having chlidren almost at 40s, most because of economy and society things. We are having an explosion of syndromes in children because of that. So, what we have to do to take care of our gametes and have health children even being in late 30s or early 40s?

I'm asking all of that because that topic I interests me a lot and I finally found a good site/community talking about it. I'm just an ignorant young boy starting medical school asking all that.

Posted by: Just Someone at March 11th, 2021 12:27 PM

Sorry for my bad english. I'm not north american.

Posted by: Augusto Franco at March 11th, 2021 12:41 PM

Hi Augusto, thank you very much for asking.

''These results clearly indicate that, if health status and biopsy conditions are controlled, the replicative lifespan of fibroblasts in culture does not correlate with donor age.''

Why is that?....It seems that replicative potential can be uncoupled from donor age; thus, there is a discrepancy between them/are uncorrelative. The why is hard to say, but from this replicative lifespan is independent from actual chronological age. It's one more paradox.

They say it does not correlate with donor age, but I believe it's not 100% true, because in some ways it does correlate; at least, when reaching very old age. The replicative potential becomes one limit as you are near the end of life, to say otherwise is saying that replicative lifespan as no say on end of life. If cells can't replicate anymore then it stops. Now why would it then possible to make the same number of replication between a young donor vs an old donor is the knot. Possibly, when extricated from the donors, this propriety is lost; whereby 'in vivo' this replication potential correlation/link to donor age stands ; but ex vivo (outside body) and in vitro, it doesn't. It's why there can be confusing results between in vivo or ex vivo/in vitro studies.
The old cells are not necessarily 'old' per se, they can be rejuvenated and not be old; as like daughter cells from mother cells dividing; epigenetically speaking they would be older...but that can be uncoupled from mitosis/mitotic capability/replication pontential/lifespan. That's still an area that is very grey-ish though. It means independent processes.

About healing/reversing aging, it's true that replacing them with Young cells and with an infinite stem cell (that differentiated into new Young cells) is a possibly solution to circumvent the limits. But, so far, stem cell replacement/continuous stem cell niche replacement was not enough neither; studies that had stem cell replacement/injection in mice saw about 20% lifespan extension and health improvement. It means it's not enough to overcome the aging process; or that we need much more fetal-like/0-age stem cell replacement/injection. If you inject 'old stem cells' (epigeneticall speaking) it will never work; the stem cells must be Young both mitotically and epigenetically speaking (because even stem cells age).

About gametes, its paradoxal also, because age at conception has an effect on whether child lives longer or not, becomes sicker/quicker or not. For example, older fathers giving longer telomeres but 'aged sperm/DNA defects in older sperm'. Gametes and sexual germ cells (such as those in testis and ovaries, though female sexual repoduction system is limited in ovules/does not use telomerase), male system use the 'telomerase' to continuously increase teh telomeres in the spermatozoid cells and thus 'continuous sperm' formation for whole life (well almost because andropause is real, just like menopause). What we have to do, is reverse the epigenetic clock of our sexual reproduction cells and remove the DNA defects that happen with time as the donor becomes older and so does the cell; and that's not small order, but tall.

Just a 2 cents.

Relationship between donor age and the replicative lifespan of human cells in culture: A reevaluation

PS: For example, a man of 40 could measure his spermatozoid epiage...and generally healthy sperm (with less defects) is about 25 years old epigenetically speaking...thus Younger then the host himself (he could be 40 years old epigenetically or 50....or 30 in most of his organs...but his semen/sperm is 25 - Not 0 neither in age. Thus, it ages too, just is lessed aged from the start). Men that are infertile may have accelerated epigenetic age in sperm or carry much more DNA defects in it - irrespective of how old they are themselves. But if they are Older, And, they are infertile, then it'S quite...there is older epigenetic age and Also more DNA defects (from age); this can create 'unhealthy/quality-compromised' sperm, that is either too old or too damaged or both (for example, the spermatozoids are motionless/or swim wrong or they have 'deformities'; this will mean compromised DNA in child). Telomeres length extension 'given to child' will be the 'compensation' for (being) old sperm.

Posted by: CANanonymity at March 11th, 2021 4:24 PM

PPS: A few other ones that can contradict this.

Donor age reflects the replicative lifespan of human fibroblasts in culture

Relationship between in vivo age and in vitro aging: assessment of 669 cell cultures derived from members of the Baltimore Longitudinal Study of Aging

''These studies revealed a trend (approaching statistical significance) toward low proliferative potential as donors aged. Interestingly, samples obtained from donors who had a history of ***skin cancer at the time of biopsy had a significantly lower doubling potential*** than those from donors who did not.''

Effects of donor age on the expression of a marker of replicative senescence (EPC-1) in human dermal fibroblasts

Posted by: CANanonymity at March 11th, 2021 4:30 PM

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