Cellular Rejuvenation

An interesting step forward in glass… making skin cells younger in cultures.

It leaves open the question of how to do this in a living animal. It might be trivial, or lethal. So more work on that front for sure.

https://elifesciences.org/articles/71624

Multi-omic rejuvenation of human cells by maturation phase transient reprogramming

Diljeet Gill, Aled Parry, Fátima Santos, Hanneke Okkenhaug, Christopher D Todd, Irene Hernando-Herraez, Thomas M Stubbs, Inês Milagre Is a corresponding author , Wolf Reik Is a corresponding author
Babraham Institute, United Kingdom; Chronomics Limited, United Kingdom; Instituto Gulbenkian de Ciência, Portugal; Altos Labs, United Kingdom
Research Article Apr 8, 2022

Abstract
Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming, somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first ‘maturation phase transient reprogramming’ (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells temporarily lose and then reacquire their fibroblast identity during MPTR, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that more extensive reprogramming does not necessarily result in greater rejuvenation but instead that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.

Basically they reset the biological clock by about 30 years, but do not revert the cell to a precursor foetal type that doesn’t know what function it is to do in the mature body yet.

Methylation is the process that marks certain genes to be turned on or off. Their description implies some aging defects are caused by methylation errors or artifacts that can be reset to a more neutral starting point.

This article explains it all more and with a bit of a downer:

https://www.lifespan.io/news/partial-reprogramming-rejuvenates-human-cells-by-30-years/

Exposing these cells to the OSKM factors was performed with a doxycycline-activated lentiviral package. While this method cannot be safely and effectively used inside a human being, it did allow the time of exposure to be carefully controlled, and such careful control is necessary; 10 days of exposure did not epigenetically rejuvenate cells as well as 13 days of exposure, but the researchers showed that too much exposure (15 and 17 days) led to cellular stresses that aged the epigenome once again. This study had only a few donors, and results after 13 days varied greatly by person.

This does leave open the possibility of rejuvenating cells in culture, then injecting them into a person. Cells injected have been shown to preferentially take residence in tissues of their type (though who knows how perfectly…).

However, it is feasible that such an approach could be used for the development of cell cultures that can be re-introduced back into an older person. This experiment used fibroblasts, which form collagen, so it is reasonable to imagine a world in which such reprogrammed cells are developed as a therapy against wrinkles and other effects of the aging extracellular matrix. This approach may one day be used to create viable, rejuvenated populations of muscle (incluluding cardiac muscle) and brain cells, and such freshly reprogrammed near-somatic cells may ultimately be the best option in many clinical applications.

Still, it is an interesting step toward repair of the damage of aging.

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About E.M.Smith

A technical managerial sort interested in things from Stonehenge to computer science. My present "hot buttons' are the mythology of Climate Change and ancient metrology; but things change...
This entry was posted in Biology Biochem, Human Interest, Science Bits. Bookmark the permalink.

8 Responses to Cellular Rejuvenation

  1. beng135 says:

    The Malthusians aren’t gonna like this.

  2. David A says:

    There is another way to accomplish much the same safely now…

    It is long, so have provided a index.
    Introduction to fasting
    02:09 the myth about fasting makes you feel tired
    04:37 Why did we stop listening to the body about when should we eat?
    06:03 Going back to the history of humankind and the genetic adaptation to different diets.
    12:00 metabolism, how does the body utilize carbohydrates, proteins and fats for energy?
    19:04 the importance of insulin
    23:20 the body has adapted to fasting
    25:32 fasting and Growth Hormone
    27:53 Autophagy
    31:49 Stem cells in bone marrow get activated when they are in fasting state.
    35:10 fasting is shown to be benefit patients with cancer
    37:55 fasting could help fight autoimmune conditions
    41:08 Drink a lot of water and add some salt and Magnesium when fasting
    42:38 Hunger comes and goes, and it is due to ghrelin
    43:15 Who should do the long fast and who should do the intermittent fasting?
    46:17 How does the body know that you didn’t eat? The function of NAD+ and longevity genes
    49:23 Vitamin D’s function in gene expression
    52:17 The importance of eating the right food. Which food is right for you?
    54:44 Meditation helps lengthen your telomere, lack of sleep shortens them (the function of melatonin)
    55:58 Proteins, Insulin-Like Growth Factor-1 and mTOR
    57:38 How much protein do you need? 0.35 grams per pound = 0.78 grams per kilo (≈ 50 grams per day)
    58:50 GH receptor deficiency (Laron syndrome) in Ecuador is associated with a reduced risk of cancer and type 2 diabetes.
    60:25 Different diets turn on and off different genes
    61:36 Aging is a disease
    65:20 Back to the evolution of a human species and genetic adaptation to diets (the impact of the agricultural and industrial revolution to our health)
    67:38 What needed to change in our diet?
    72:28 A little bit high blood sugar is fine, high insulin level is worrying
    75:22 blood glucose, triglyceride, LDL and HDL (HDL to triglyceride ratio)
    76:45 A study about fasting done in monkeys

  3. David A says:

    Some of the most cogent sections…

    23:20 the body has adapted to fasting
    25:32 fasting and Growth Hormone
    27:53 Autophagy
    31:49 Stem cells in bone marrow get activated when they are in fasting state.
    35:10 fasting is shown to be benefit patients with cancer
    37:55 fasting could help fight autoimmune conditions

    54:44 Meditation helps lengthen your telomere, lack of sleep shortens them (the function of melatonin)
    55:58 Proteins, Insulin-Like Growth Factor-1 and mTOR

    And a study specific to stem cells, however the medical industry makes zero money when folk fast, so don’t expect major promotion of this understanding.

  4. beng135 says:

    David A, structured fasting can also help, even cure Type 2 diabetes.

  5. philemon says:

    Interesting. Plastic surgery has long been aware that silicon sheets help reduce scarring.

  6. E.M.Smith says:

    @David A:

    At about 30 years old, a friend was having significant blood sugar hypoglycemia issues.

    I decided to explore food driven blood sugar control using me as the test animal. At first, with a lifetine of eating “normal” foods behind me (I.e. meat, birds & potatoes, vegatables, fish; very little processed stuff), pretty much all food excursions did little.

    So I spent about 2 months eating a high carbs and sugar diet, low protein and mid level fats (often processed hydrogenated fats in things like snack pastries junk food). Then “the shakes” started… IF I didn’t have a constant influx of carbs, I’d get a low blood sugar excursion and mild “sugar shakes”. Scared me a bit. Now how do I get out of this trap?

    Well, a cold turkey back to meat & potatoes didn’t work (big shakes and brownout). So the slower road…

    First dropped the junk foods, sodas, and sugars. Added some more noodles at low sugar times. After a couple of weeks, then started adding more buttered vegetables and meats. Next, lowered breads and pasta as “sugar shakes” were no longer a problem. After a couple of months I was back near to my former robust diet tolerance. (Eventually lost the pounds I’d added too…)

    My conclusion was that what is now commonly named “metabolic syndrome” and a lot of “hypoglycemia” is caused by a junk food rich diet heavy on sugars and carbs; over months. It pushes your metabolusm into an ‘edge case’ with screwed up enzyme levels. For me, at least, cured by eating real more traditional foods like meats, birds, fish, vegetables, natural fats.

    This experiment was the launching point for my Dig Here! into the horrors of trans fats and fructose. Two things to be strongly avoided and common in processed foods.

    It was also the antithesis of fasting. It required constant inputs of carbs to hold a stable blood sugar level (I susppect due to trans fats binding fat metabolizing enzymes while carbs were forced into a “store as fats” pathway due to the high peak level, but then the enzymes being at high levels when the rapid carbs dropped to low levels…)

    Spreading out the carb intake over time (clipping the peaks) and shifting from fast carbs (sugars) to slower carbs (noodles) with more protein pathway foods got rid of the blood sugar peak / trough cycle and let “store as fat” pathways back off. But it took months to clear the trans fats and get effective “fat to blood sugar or ketone body” metabolism back on line. THEN I was able to effectively fast by skipping a meal or two again…

    I’m now back to my “food camel” mode. I can skip any meal and not notice. If needed, not eating for a day or two is no big deal. Mildly annoying at most as I shift to ketone body metabolism (“keto diet” effect).

    I don’t like sugars most of the time. Black coffee, no sodas, water with meals. Mostly meat, birds or fish with buttered vegetables & salads. Some bread (about 2 slices a day if that) and some potatoes & beans. Just foods you would find on a farm in the 1700s…. It is just what I like to eat, no big plan.

    I was just very surprised to discover how much what I had thought was my innate nature; was instead a product of food choices.

  7. David A says:

    EM, WOW, you were 30 years ahead of most in figuring out that the SAD ( Standard American Diet)
    is not a road, but THE road to diabetes, heart disease and heavy medical and hospital bills. BTW, research shows that the SAD diet is even harder on Asians.

    EM, says,
    “Spreading out the carb intake over time (clipping the peaks) and shifting from fast carbs (sugars) to slower carbs (noodles) with more protein pathway foods got rid of the blood sugar peak / trough cycle and let “store as fat” pathways back off. But it took months to clear the trans fats and get effective “fat to blood sugar or ketone body” metabolism back on line. THEN I was able to effectively fast by skipping a meal or two again…”

    If I am reading the literature correctly there are short cuts to keeping the metabolism and blood sugar balanced. I think it is directly spoken of in the long video link I gave. I think part of the answer is to take in healthy fats, just prior to the proteins, which alters the protein to sugars metabolism pathway.
    My own experience was a three day fast, (blood tests showed Ketosis on day two) to an immediate no carb diet for three weeks. ( I lost 24 pounds )

    If you have a chance to watch the video, note that maximum atophagy benefits kick in on day 3 of a fast. That is when the impressive stem cell development, cellular replenishment, telemere lengthening, hormone producing magic really kicks in.

    23:20 the body has adapted to fasting
    25:32 fasting and Growth Hormone
    27:53 Autophagy
    31:49 Stem cells in bone marrow get activated when they are in fasting state.
    35:10 fasting is shown to be benefit patients with cancer
    37:55 fasting could help fight autoimmune conditions
    54:44 Meditation helps lengthen your telomere, lack of sleep shortens them (the function of melatonin)
    55:58 Proteins, Insulin-Like Growth Factor-1 and mTOR

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