This is actually super cool. Yesterday, an extremely exciting academic study from the Netherlands Cancer Institute in Amsterdam described tremendously exciting leaps in anti-aging drugs, often thought to be a holy grail of biological science.
Senescence occurs when the cell is too damaged to continue dividing into more cells, but is stopped from completing apoptosis for some reason. This is tremendously interesting, but not super relevant to understanding the article. To understand telomere shortening, first we need to talk about how DNA works — cells in your body are constantly dividing to refresh the tissues that they make up.
Because of this, chemotherapy causes your hair to fall out and GI distress — those cells divide more quickly and are thus killed by the chemotherapy drugs. The shortening telomeres is hypothesized to be connected with aging — studies show that people with longer telomeres live longer than those with shorter telomeres.
As mentioned above, one of the ways that cells can enter senescence is when their telomeres are shortened beyond usefulness — the cell may or may not still be working well, but it has lost the ability to divide.
Lots of studies about longevity center around trying to lengthen the telomeres or slow down the rate that they decay. Welcome back! Senescent cells usually leak lots of nasty chemicals that cause inflammation and damage in our bodies and can also develop into tumors.
So, how do we fix senescence? Instead, they found just the levels of both that they expected! To figure out what was blocking it, they looked for proteins that were being generated in higher numbers than normal in the cell that might be jamming up the works of the apoptosis mechanisms.
They started looking at what FOXO4 actually does in senescent cells, and one important thing was that it liked to grab on bind to a protein called p Not so fun fact, most people have a suprisingly huge number of cells that can become tumorous in their lifetime, but our cells are so good at self regulation that they nip it in the bud with p53 before it can hurt us. Go cells! An important part of this is that FOXO4 lives in the nucleus of the cell and p53 does its work at the mitochondria — two different parts of the cell.
The outcome of this in mice was incredible. Because of the damage doxorubicin does, it creates large numbers of senescent cells. They reversed a substantial part of the damage done by the chemotherapy!
They also saw kidney dysfunction due to age reversed as kidneys grew more healthy with the senescent cells killed off, healthy cells could flourish. While these are amazing results, the real kicker is the naturally aged mice — lots of studies limit themselves to genetically modified mice, which introduces other variables that might affect the outcome of the study.
Save my name, email, and website in this browser for the next time I comment. Notify me of follow-up comments by email. Notify me of new posts by email. I read the paper, and could not find any mention as to the dosage they used in the experiments. Am I not reading the paper right, or is the dosage not mentioned? I was mostly joking. Very interesting article, btw.
Thank you for posting. Oh, how tired I am of people coming up to me in clubs and trying to flog me illicit peptides. And will it ever? So in case of a progressing untreatable end state case of aging I should be allowed to try it too. Aging is too important to disregard it as we do. So, the mice act younger. Do they actually, you know, live longer?The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging.
Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored.
Here, we identify FOXO4 as a pivot in senescent cell viability. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity.
Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored. Abstract The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging.
Publication types Research Support, N. Gov't Comment.Do you want to live a longer life in good health? Simple practices can make some difference, such as exercise or calorie restriction. But over the long haul all that really matters is progress in medicine: building new classes of therapy to repair and reverse the known root causes of aging.
The sooner these treatments arrive, the more lives will be saved. Today, another research group announced their entry to the field of senescent cell clearance as a means to treat agingalong with the intent to commercialize their novel method of achieving selective destruction of senescent cells in aged individuals.
Senescent cells accumulate with age as a result of the normal operation of living tissues: cells become senescent when damaged or when they reach the Hayflick limit on replication. Near all are destroyed, either through the programmed cell death mechanism of apoptosisor by immune cells attracted by the signal molecules generated by senescent cells.
Unfortunately, some linger, resistant. The number of these cells grows over the years, and the signals they generate start to create harmful outcomes in nearby cells and tissue structures, and in addition spur rising levels of chronic inflammation. The increasing presence of senescent cells is one of the root causes of degenerative aging and directly contributes to many specific age-related diseases. The best and most direct approach to the phenomenon of cellular senescence is to periodically destroy these cells, reducing their numbers to the greatest extent possible.
These numbers are never enormous, perhaps a few percent of most tissues in late old age, depending on the details.
A FOXO4-DRI Breakdown — Senescent Cell Apoptosis
Removal can proceed as slowly as needed to be safe in older individuals if there are risks of lysis side-effects due to the amount of cell debris generated by senescent cell destruction. While senescence has short-term roles to play in tumor suppression, by shutting down the ability to replicate in potentially cancerous cells, and in wound healingthese cells have no clear and evident long-term use in the body.
So a treatment that gets rid of near all of these cells, undergone once every few years, would in fact be a narrow means of rejuvenation. It would make aged tissues less aged. This has been demonstrated in studies of senescent cell removal showing life extension in miceas well as those that have demonstrated specific improvements and reversals in the pathology of various age-related diseases and aged tissues.
The methodology developed by the researchers noted here is, at the very high level, analogous to that involved in some of the senolytic drug candidates evaluated to date - though it has the merit of having far fewer side-effects per this report.
It involves sabotaging one of the mechanisms that lingering senescent cells use in order to resist the fall into apoptosis, but which in normal cells has no important role to play.
Thus drug molecules can be delivered everywhere, and will only produce significant effects in cells that are senescent. In the case of drugs like navitoclaxthat mechanism involves inhibiting bcl-2 family proteins.
The mechanism here is quite different, involving FOXO4's influence on p53but I wouldn't be surprised to see it turn out to be a part of the same system of inhibition of apoptosis. Almost all cellular mechanisms can be influenced in many ways, by tinkering with the activities and actions of many directly and indirectly involved proteins, and it is not unusual for research groups initially working on a diverse set of proteins to find that they end up in the same place at the end of the day.
Peptide targeting senescent cells restores stamina, fur, and kidney function in old mice. Regular infusions of a peptide that can selectively seek out and destroy broken-down cells that hamper proper tissue renewal, called senescent cells, showed evidence of improving healthspan in naturally-aged mice and mice genetically engineered to rapidly age.
The peptide took over four years of trial and error to develop and builds on nearly a decade of research investigating vulnerabilities in senescent cells as a therapeutic option to combat some aspects of aging. It works by blocking the ability of a protein implicated in senescence, FOXO4, to tell another protein, p53, not to cause the cell to self-destruct.
By interfering with the FOXO4-p53 crosstalk, the peptide causes senescent cells to go through apoptosis, or cell suicide. We treated mice for over 10 months, giving them infusions of the peptide three times a week, and we didn't see any obvious side effects.
FOXO4 is barely expressed in non-senescent cells, so that makes the peptide interesting as the FOXO4-p53 interaction is especially relevant to senescent cells, but not normal cells. Results appeared at different times over the course of treatment.FOXO4 is a member of the forkhead family transcription factors O subclass, which is characterized by a winged helix domain used for DNA binding. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation.
FOXO transcription factors have been shown to be the down downstream effector molecules of insulin-like growth factor IGF signaling pathway. In the absence of insulin, PI3K is inactive, so the FOXO homolog daf is able to translocate to the nucleus and turn on many genetic pathways associated with longevity in the roundworm Caenorhabditis elegans. FOXO4 can bind with p53 protein to induce cellular senescence.
Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation. In gastric cancers GCit has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ.
It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis by downregulating vimentin. In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4. This article incorporates text from the United States National Library of Medicinewhich is in the public domain.
From Wikipedia, the free encyclopedia. X chromosome human . National Center for Biotechnology Information, U. National Library of Medicine. Genes Chromosomes Cancer. Nature Reviews Molecular Cell Biology.
The Biochemical Journal. Bibcode : PNAS. The Journal of Biological Chemistry. Nucleic Acids Research. Bibcode : Natur. Cancer Research. BMC Cancer. Asian Pacific Journal of Cancer Prevention.
Cancer Res. Cookson MR ed.
Category Archives: FOXO4-p53
Bibcode : PLoSO Bibcode : PNAS Crossley LJ Transcription factors and intracellular receptors. LRH-1 SF1. Categories : Genes on human chromosome X Forkhead transcription factors Aging-related proteins. Namespaces Article Talk. Views Read Edit View history. Help Learn to edit Community portal Recent changes Upload file. Download as PDF Printable version. Gene location Human. Gene location Mouse. X chromosome mouse .
RNA expression pattern.I have covered anti-aging research on this blog a few times in the past: partly because aging reversal can often imply hair loss reversal; and partly because I also cover medical items of interest once a month. This week was one of the best ever in anti-aging research, especially for mice and their fur.
For many years, scientists have known that the quantity of senescent cells i. More recently, research has suggested that senescent cells also damage other nearby healthy cells. So, not surprisingly, some scientists have conducted experiments to see if removing these old senescent cells ideally, without damaging other normally functioning cells reversed signs of aging and increased life expectancy.
A few experiments in mice have suggested the answer to be in the affirmative e. There is now even a name senolytics for the class of drugs that can kill senescent cells.
This week, a groundbreaking study led by Dr. Key photos below green arrows on rightmost column show hair regrowth in almost all mice after FOXO4 peptide ingestion :. The team behind this research plans clinical trials in humans in the near future. There are literally s of articles on this development, and various scientists from other countries have been quoted as saying that this development is potentially a huge breakthrough in anti-aging science.
Two contrasting sources here and here. Addendum 1: In case anyone got the wrong idea from my recent post on obesity perhaps benefiting scalp hair, this study is worth reading. I have covered anti-aging Harvard-based Australian researcher Dr. David Sinclair widely associated with resveratrol once on this blog before here.
Sinclair in some ways is the Dr. George Cotsarelis or Dr. Ken Washenik of the anti-aging world. You decide what I mean by the above sentence. Note that there is also a Dr. Rodney Sinclair who is a famous hair loss researcher that I have covered a few times on this blog.
He is also from Australia. In recent years, a number of scientists have been researching the fascinating subject of whether older people can be rejuvenated by the infusion of blood from the young! Billionaire Peter Thiel is especially interested. However, one major problem with this strategy for older non-wealthy people is that there might not be enough young healthy donors with the correct blood type willing to donate at reasonable prices.Hockey parlays are figured out by calculating the payout for the first game, based on the money line, then applying that amount to the next game and so forth.
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Rules and details vary greatly by casino so be sure to shop around to find those that appeal to you. Nevada sports books are not permitted to accept wagers on presidential elections, the Academy Awards or the winner of the TV show "Survivor. They are not real betting lines. Under state law, wagers must involve the outcome of "athletic contests" rather than elections or votes of any kind. This means you cannot even bet on who will win awards such as the Most Valuable Player, Rookie of the Year, Cy Young and the like.
Even so, "wacky" proposition bets can sometimes be found in Las Vegas sports books. They are often linked to the Super Bowl or another major sporting event.
For instance, in Super Bowl XXXV gamblers could bet on whether the Ravens would score more touchdowns than the Chicago Blackhawks scored goals on Super Bowl Sunday -- and that was just one of countless "wacky" propositions. As another example, to generate interest in Monday Night NFL games, many sports books offer odds on which player will score the first touchdown in the game.
These "wacky" bets can be lots of fun, but odds and details vary tremendously by casino, so read the fine print before getting involved. As an email subscriber, you have immediate and exclusive access to our best rates: our Insider Pricing deals.
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The browsers we support are: Internet Explorer 8 Internet Explorer 9 Internet Explorer 10 Firefox Chrome Safari Close Message Inside Gambling Jackpots Slot tournaments Poker Bingo Las Vegas betting line Futures Sports books Sports betting Sports news How to gamble Gaming news You Also Might Be Interested In Las Vegas Restaurants For your Vegas Vacation Las Vegas hotels Las Vegas show tickets Las Vegas tours Las Vegas nightlife Las Vegas golf courses Sports Betting table.
Learn all the basics to sports betting on this page along with a few advanced methods. This guide is provided for informational purposes only. This is not a betting site. DriverOddsJeff Gordon4-1Jeff Burton15-1Casey Atwood100-1 Auto racing matchup propositions also are available, in which two drivers are paired against each other in a head-to-head wager, with a betting line on each driver set by the oddsmaker.
Betting lines can be found on NASCAR races as well as on the various open-wheel circuits.
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Too many people submit spam reports and too many people engage in negative SEO for me to invest too much in unnatural links these days. If you want to rank in Google with any confidence in the long-term, you are going to have to INVEST in GOOD, IN-DEPTH content, and a few GREAT links.
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