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Old human cells rejuvenated in breakthrough discovery on ageing

senescent cells rejuvenation

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#151 Rocket

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Posted 27 January 2018 - 02:05 AM

I was doing, lately, 600 to 900 mg daily. Put on hold because of 2nd metatarsal fracture 3 weeks ago. Read conflicting things about resveratrol and bone. I really liked the R+C combo over straight R. I think once I start again that I will add in GH secretogogues since I am on them now for healing and like the results. Walking barefoot painfree in just over 2 weeks. Have not lost any muscle despite reduced workout schedule.

Why do you cycle it, Nate?

Edited by Rocket, 27 January 2018 - 02:08 AM.


#152 Nate-2004

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Posted 27 January 2018 - 10:21 PM

Because I don't think the benefits to a lot of the things that show benefits either in vitro or in vivo come from taking those things chronically.  I think you end up with a diminishing returns that may even result in more harm than good, if not on the body then on the wallet.

 

This is just a general statement. I do think you can accomplish what you're trying to, at least with resveratrol, with just a day or so of taking it while suppressing the relevant enzymes. I have literally no evidence for this other than just a hypothesis about why it works so well in vitro and yet it's useless so far based on all the in vivo studies that have people taking smaller daily doses over a fairly long period of time. Also people who take it repeatedly day in and day out often report problems like joint inflammation. Maybe it has some kind of bell curve effect on inflammation for whatever mechanical reason. Also as far as having the effect on senescent cells that we want it to have, I don't see why it would need a continuous administration day in and day out. This isn't like trying to boost NAD+ or trying to keep up levels of various micronutrients. This is a therapy that may only need a day of dosing round the clock (based on the earlier linked studies and graphs on how long it stays in the system) to do the work.

 

I also think the same thing about antioxidants. Antioxidants are as much about cycling as they are about timing. Keeping them as far away from exercise as possible, etc.

 

Less is more. And in this case, more punctuated, intermittent dosing.


Edited by Nate-2004, 27 January 2018 - 10:27 PM.

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#153 Iuvenale

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Posted 10 February 2018 - 10:10 PM

Is there any empirical evidence for this cycling idea?

#154 Nate-2004

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Posted 11 February 2018 - 07:02 PM

Yes and I linked the source somewhere on this site a couple of times and now it seems googling is not resulting in my finding the publication right now.

 

 



#155 QuestforLife

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Posted 22 February 2018 - 04:39 PM

Has anyone got any further in trialing resveratrol for senescent cell rejuvenation?

 

From the papers I've read (notably 'Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-does study in healthy volunteers', full text available via Sci-Hub, and 'Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventative agent', free text online ) it takes around 5g of resveratrol on average (large variation here; SD was 73% of the mean) to get a blood level of 2.4uM/L.

 

Now according to the paper that started this thread they got their in vitro effects with 5uM/L for 24 hours. To get to the 5uM figure probably doesn't require 10grams, as the Cmax seems to rise at a greater than linear relationship with dose, but this is my guesswork based on eye-balling the plots.

 

The next problem is the 24 hour duration required. Believe it or not the half life when taking 5g averaged out at 8.5hours - though this varied considerably (SD was 95% of the mean) - and might be due to metabolites of resveratrol being converted back (?). I think for most of us we should assume a half life of around 4 hours when taking 5g.

 

So if you dosed 5grams every 4 hours you'd quickly build up the amount in your system to between 10g max and 5g min. Over 24 hours you'd ingest 30grams. I realise this is a heroic dosing schedule, but if anyone is wondering why they haven't been seeing any results, it could be that you've massively underestimated how much of this stuff you need to take!

 

I must also stress caution as some people metabolise resveratrol slower; if you're a slow caffeine metaboliser you might be able to assume a half life of 8 hours instead - and this would be safer to avoid potential side effects (if any).

 

If we try the above dosing protocol and it still doesn't work then there might be an issue with metabolites interfering with the effects (unlikely?), or perhaps we just don't have enough senescent cells to feel if they are rejuvenated, or it might be that high levels of resveratrol in the blood is not enough to guarantee all required tissues are reached. But given the enormous potential of turning senescent cells back into young cells, I think we should try.

 

 


Edited by QuestforLife, 22 February 2018 - 04:41 PM.


#156 Nate-2004

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Posted 23 February 2018 - 01:40 PM

I was dosing high for a 12 hour period by basically taking 600mg orally and then mixing 1200mg T-Resv with an appropriately soluble amount of ethyl alcohol and heavy cream. Then I would drop that under my tongue every 30 mins or so and take another 600mg orally every couple hours. Not sure how much that would have gotten me to as far as a Cmax goes but I ran out of the stuff after a few rounds of doing that. That was easy for 12 hours on a lazy Sunday but 24 hours means no sleep haha. 

 

The only thing I notice is that my hair *seems* thicker and looks thicker in the back and in the mirror. It's also harder to style lately partly due to that. This could all be just perception but that perception has lasted more than a couple of weeks now and I'm skeptical about my own perceptions.


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#157 ceridwen

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Posted 23 February 2018 - 02:55 PM

Well seeing as you have a tremor this is very informative. It's not as if you had nothing wrong with you. Clearly it doesn't help the brain then
I don't like the way it's said to remove amyloid but shrink the brain. In fact that completely put me off!
Sorry no reference but I read about this in Science daily

#158 Nate-2004

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Posted 23 February 2018 - 03:29 PM

Well seeing as you have a tremor this is very informative. It's not as if you had nothing wrong with you. Clearly it doesn't help the brain then
I don't like the way it's said to remove amyloid but shrink the brain. In fact that completely put me off!
Sorry no reference but I read about this in Science daily

 

I've had a tremor since the age of 12...

 

Yeah I can't imagine that developed as a result of senescence at such a young age but then again who knows how that develops. Nobody knows what causes essential tremor. The only thing that subdues it is a ketogenic diet for some reason, even then only after two weeks of adaption to ketones. I'd like to know why because that could lend a clue. BHB possibly, not sure.



#159 ceridwen

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Posted 23 February 2018 - 04:00 PM

I don't know. I had memory problems since about that age. I used to joke that I had the beginnings of Alzheimer's since puberty. Now it suddenly seems very serious. I found transhumanism due to that problem if fact. Now nothing really seems to work. Correct your tremor before it's too late. I don't want to scare you or anything. Hope it's NOT Parkinson's though
Low carb diet not working for me. Fat makes me sick. I have APOE4
Low carb diet not working for me. Fat makes me sick. I have APOE4 plus a couple of early onset genes.
Low carb diet not working for me. Fat makes me sick. I have APOE4 plus a couple of early onset genes.
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#160 recon

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Posted 23 February 2018 - 04:07 PM

Well seeing as you have a tremor this is very informative. It's not as if you had nothing wrong with you. Clearly it doesn't help the brain then
I don't like the way it's said to remove amyloid but shrink the brain. In fact that completely put me off!
Sorry no reference but I read about this in Science daily

I think the brain shrinking effect of resveratrol was discussed before. Many hypothesis indicates that the shrinkage was due to lower inflammation of the tested subjects.

“A puzzling finding from the resveratrol study (as well as immunotherapy strategies for Alzheimer’s under investigation) is the greater shrinkage of the brain found with treatment. These new findings support the notion that resveratrol decreases swelling that results from inflammation in Alzheimer’s brain,” says Turner. “This seemingly paradoxical effect is also found with many of the drugs that are beneficial for patients with multiple sclerosis - another brain disease characterized by excessive inflammation.”
- https://gumc.georget...heimers-Disease
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#161 Nate-2004

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Posted 23 February 2018 - 04:33 PM

I don't know. I had memory problems since about that age. I used to joke that I had the beginnings of Alzheimer's since puberty. Now it suddenly seems very serious. I found transhumanism due to that problem if fact. Now nothing really seems to work. Correct your tremor before it's too late. I don't want to scare you or anything. Hope it's NOT Parkinson's though
Low carb diet not working for me. Fat makes me sick. I have APOE4

 

Keto also helps a ton with cognition and reversing some aspects of progression with Alzheimer's. It's a super low carb ultra high fat diet for sure but a lot of people are really misinformed about what to eat. It requires loads of nuts, avocado, fibrous leafy greens. A lot of people just eat bacon, beef, cheese, eggs and over cooked veggies mixed in, this is not good. Stick with fatty fish, like salmon, good nuts like walnuts and almonds that contain considerable amounts of magnesium and tocopherols. Eggs and meat are fine but the main goal is to minimize protein and carbs while emphasizing healthy fats and fiber, and most of all to keep ketone levels (use a blood test meter) up to therapeutic levels of 3.0. The mechanism is probably unknown but the likely cause is increased BHB levels. 

 

If you were getting sick, that was either because you weren't eating right, you were adapting to ketosis which takes a few days and has flu like symptoms, or you were not supplying yourself with enough water and electrolytes like sodium, calcium, magnesium and potassium, many of which come with the leafy greens and nuts.

 

See this conservative, but promising review of keto's effects on Alzheimer's patients. 

 

https://www.scienced...213453016301355


Edited by Nate-2004, 23 February 2018 - 04:37 PM.

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#162 QuestforLife

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Posted 23 February 2018 - 04:37 PM

Interesting Nate, 1200 -1800mg would put you at only a fraction of the in vitro study concentration, but dosing every half hour would build the amount in your system very rapidly. I wouldn't be surprised if you did achieve biologically relevant concentrations, albeit for a shorter time period than in the study. So did you dose another whole 1200mg every 30 mins, or was it just a fraction of that amount until the 1200mg ran out?

I used up about 2.8g of liposomal resveratrol in 14 hours or so, and didn't really notice anything. I plan to repeat the experiment with the entire remainder of my supply over 24 hours (around 15g) and see what that does.

#163 Nate-2004

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Posted 23 February 2018 - 04:41 PM

Yeah I dosed that sublingually with a dropper, 4ml, every 30 mins to an hour until that 1200mg (total in the vial) ran out. Took about 8 to 12 hrs. I need to rethink this I guess. If/when I do this again I may get it from a liposomal source, though I don't know how much I can trust those sources, and try to dose for 16 hours straight with as much as possible. Not sure how many grams are in their bottles though.


Edited by Nate-2004, 23 February 2018 - 04:43 PM.

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#164 QuestforLife

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Posted 23 February 2018 - 05:03 PM

Nate, the Actinovo bottles have 4.5g in the 250ml bottle. But I don't think you necessarily need liposomal, I just so happen to have it.

Ceridian, I've mentioned this before but all APOE4 carriers need to be on rapamycin. See Alan Green' s site.

#165 Nate-2004

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Posted 23 February 2018 - 06:28 PM

WTF is unfriendly about my post above? LOL

 

Anyway, keep in mind I'm also drinking a smoothie with 4 stalks of celery and 100g parsley the night before, drinking coffee and also chamomile tea later on in the day.  I'm also taking quercetin and curcumin with bioperine. All these things should help greatly with inhibiting the enzymes that metabolize resv.


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#166 QuestforLife

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Posted 23 February 2018 - 06:55 PM

Yes all those things will help for sure. But the point of my long post above was to show that you need more than 5g in your system, either in one big go or built up within a sub half life timescale, if you want to have a chance of acheiving what they did in vitro (and then you need to sustain it for perhaps 24 hours).
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#167 QuestforLife

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Posted 25 February 2018 - 09:26 AM

Nate, the Actinovo bottles have 4.5g in the 250ml bottle. But I don't think you necessarily need liposomal, I just so happen to have it.


I've just drunk my first bottle. Thinking about it, liposomal may be an advantage because it gets rid of the variation in the amount you absorb, quoted in those studies.then it's just the rapid digestion by the liver you have to contend with.
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#168 QuestforLife

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Posted 26 February 2018 - 09:11 AM

Well that was disgusting.

 

8 am: drank 250ml liposomal resveratrol (4.5g).

11 am: diarrhea.

1230 pm: diarrhea.

4 pm: Stomach feels fine. Decided to do another 4.5g bottle, but divided up into 25ml shots every 20 mins or so. No diarrhea, but the taste of all this resveratrol is really horrible. Feel tired, and skin feels different, almost as if I'm wearing it, if that makes any sense?

9am: Feel a little sick.

 

 


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#169 Nate-2004

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Posted 26 February 2018 - 04:18 PM

Eeep! Yeah wow not sure what's going on there but it could be other ingredients or it could be the resveratrol. I'm probably going to do another round of this but not liposomal.



#170 QuestforLife

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Posted 07 March 2018 - 02:34 PM

From Wikipedia on resveratrol:

 

'In 2010, GlaxoSmithKline suspended a small clinical trial of SRT501, a proprietary form of resveratrol, due to safety concerns. SRT501 was composed of microparticles (< 5um) intended to enhance absorption and was delivered at 5 grams per day, causing gastrointenstinal disorders and diarrhea in many subjects...'

 

Explains my experience with 4.5g of liposomal resveratrol rather well, don't you think?

 

In addition I was also very tired for a further 1 day.

 

I'm thinking the amount of resveratrol you need to achieve the 5uMolar concentration, there is always going to be side effects, and that pterostilbene might be a better bet. The backbone of the molecule is identical to resveratrol, as with all the resveratrol analogues in the study, the methylated side chains should enhance cellular absorption, and best of all it's much more bioavailable, so you don't need to take as much, or use liposomes.

 

 



#171 Nate-2004

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Posted 07 March 2018 - 02:43 PM

Pterostilbene is not very well studied and what little preliminary data we have shows that it raises LDL and worse yet lowers HDL, on top of that bad news it raises overall cholesterol. There's no good evidence showing the kind of results, at least in vitro, that resveratrol had. Unless I'm out of date here, maybe something has popped up in the last year or two since I last looked into this.

 

Examine had this to say:

 

In contrast to the aforementioned potencies of pterostilbene, it appears to be a relatively lacklustre antiinflammatory agent. Furthermore, while it seems more potent than resveratrol on a few parameters (antioxidative and its absorption rates) a highly extensive comparison has not been conducted; while saying pterostilbene is a 'more potent resveratrol' is not completely inaccurate, it may not apply to everything resveratrol can do.

 


Edited by Nate-2004, 07 March 2018 - 02:50 PM.


#172 QuestforLife

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Posted 07 March 2018 - 03:42 PM

 

Examine had this to say:

 

In contrast to the aforementioned potencies of pterostilbene, it appears to be a relatively lacklustre antiinflammatory agent. Furthermore, while it seems more potent than resveratrol on a few parameters (antioxidative and its absorption rates) a highly extensive comparison has not been conducted; while saying pterostilbene is a 'more potent resveratrol' is not completely inaccurate, it may not apply to everything resveratrol can do.

 

 

Hi Nate,

I regard this as a good thing - I am not interesting in an anti-inflammatory action, or even in SIRT1 activation; I just want to extend telomeres of old cells. Anything else is confusing and makes it hard for me to attribute any discerned benefits. As to the effects on lipoproteins I think they are overblown, and even if they are not, I am not going to be taking pterostilbene for a long period, just over 24 hours maybe once every 3 or 6 months.
 


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#173 Nate-2004

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Posted 07 March 2018 - 03:44 PM

 

 

Examine had this to say:

 

In contrast to the aforementioned potencies of pterostilbene, it appears to be a relatively lacklustre antiinflammatory agent. Furthermore, while it seems more potent than resveratrol on a few parameters (antioxidative and its absorption rates) a highly extensive comparison has not been conducted; while saying pterostilbene is a 'more potent resveratrol' is not completely inaccurate, it may not apply to everything resveratrol can do.

 

 

Hi Nate,

I regard this as a good thing - I am not interesting in an anti-inflammatory action, or even in SIRT1 activation; I just want to extend telomeres of old cells. Anything else is confusing and makes it hard for me to attribute any discerned benefits. As to the effects on lipoproteins I think they are overblown, and even if they are not, I am not going to be taking pterostilbene for a long period, just over 24 hours maybe once every 3 or 6 months.
 

 

 

Right but the thing is there is at least evidence for restoring "youth" to senescent cells in vitro with resveratrol and analogues, but not pterostilbene to my knowledge. I may need to reread that study maybe they did use pterostilbene.



#174 QuestforLife

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Posted 07 March 2018 - 03:50 PM

You are right Nate, they did not use pterostilbene in the study but I explained my rationale for using it above - the resveratrol analogues all worked by extending telomeres despite their varying side chains, which only seemed to impact their anti inflammatory and SIRT1 action. Therefore it is the backbone of the molecule (that was common to all) that matters. And pterostilbene has that exact same back bone, plus it has superior pharmacokinetics (because of the methylated side chains) compared to resveratrol making it a far better prospect for replicating the study in vivo.

 

It's just an idea and it may not work, but I think it is a better bet than making yourself puke/shit yourself trying to do this with tens of grams of resveratrol.


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#175 Nate-2004

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Posted 07 March 2018 - 07:58 PM

RIght but it may be better to ramp it up and dose frequently over the day rather than trying to take it all at once.


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#176 QuestforLife

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Posted 08 March 2018 - 09:25 AM

Well that was disgusting.

 

8 am: drank 250ml liposomal resveratrol (4.5g).

11 am: diarrhea.

1230 pm: diarrhea.

4 pm: Stomach feels fine. Decided to do another 4.5g bottle, but divided up into 25ml shots every 20 mins or so. No diarrhea, but the taste of all this resveratrol is really horrible. Feel tired, and skin feels different, almost as if I'm wearing it, if that makes any sense?

9am: Feel a little sick.

 

As you can see from my write up Nate, I tried both 4.5g in one go, and later another 4.5g over a number of hours. Although taking the same dose in smaller goes avoided diarrhea I still felt nauseated.

 

The other problem we have with this protocol is the lack of any metric to know its working. Perhaps a Life Length Test, which I believe includes a measure of the percentage of short telomeres?

 

I am not convinced that at my age of ~40, I would be able to tell if senescent cells were rejuvenated. Is there any literature on the rate of accumulation in different tissues for humans?



#177 Rocket

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Posted 19 March 2018 - 01:15 AM

Well that was disgusting.

8 am: drank 250ml liposomal resveratrol (4.5g).
11 am: diarrhea.
1230 pm: diarrhea.
4 pm: Stomach feels fine. Decided to do another 4.5g bottle, but divided up into 25ml shots every 20 mins or so. No diarrhea, but the taste of all this resveratrol is really horrible. Feel tired, and skin feels different, almost as if I'm wearing it, if that makes any sense?
9am: Feel a little sick.


As you can see from my write up Nate, I tried both 4.5g in one go, and later another 4.5g over a number of hours. Although taking the same dose in smaller goes avoided diarrhea I still felt nauseated.

The other problem we have with this protocol is the lack of any metric to know its working. Perhaps a Life Length Test, which I believe includes a measure of the percentage of short telomeres?

I am not convinced that at my age of ~40, I would be able to tell if senescent cells were rejuvenated. Is there any literature on the rate of accumulation in different tissues for humans?

1. That's why some people in foxo4 trial are wasting it - they aren't old enough for anything positive to come from it - only negative side effects.

2. This method is the safest between cancer medicine and resveratrol

3. Considering by 40 that things like sarcopenia are progressing then absolutely cellular rejuvenating treatments will have an effect but because its athletic performance that is lost by 40, unless you are an athlete you may not notice the slight improvement
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#178 QuestforLife

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Posted 19 March 2018 - 09:05 AM

Totally agree Rocket, people are going crazy over FOXO4-dri when it's not going to do much unless aging is well advanced.

 

Senescent cells are constantly produced in the body, and constantly cleared. It's only when the rate of production exceeds the rate of clearance that problems will start to occur. Obviously this will happen at end of life, because of replicative senescence of stem cells, and other health issues can cause this to occur early, (immune problems, inflammation, etc.) but for those like myself experiencing the first real signs of aging in early middle age, symptoms are more likely to be caused by just a general slowing down of cell replacements, as well as their internal turnover of proteins.

 

Having said all that, having a substance flood the circulatory system every few months and rejuvenate senescing endothelial cells, would be a great defence against atherosclerosis, even if it reached no other part of the body.



#179 Nate-2004

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Posted 19 March 2018 - 03:18 PM

Most people can tell if a person is in their late 30's or early 40's, the question is, why? Things begin to decline around this time, why? Grey hair, wrinkles, athletes even retire around this age. If there aren't enough senescent cells at this point to matter, then a buildup of senescent cells or SASP is not really as big of an aging factor as we thought, at least not at this point. It may still be more related to Advanced Glycation Endproducts, glucosepane mostly but also pentosidine and fructosamine. 


Edited by Nate-2004, 19 March 2018 - 03:19 PM.


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#180 QuestforLife

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Posted 19 March 2018 - 05:47 PM

Yes you can tell when someone is in their 30s or 40s as opposed to 20s but I very much doubt that has much to do with senescent cell accumulation. Yes there will be some, but the majority of cells with be somewhere in the continuum between youthful vigour and full senescence. This means they can still proliferate, if required, but more slowly that previously, and can still produce and degrade proteins, but also not as quickly. Therefore you hang onto cells for longer, and those cells turnover their internal contents more slowly. Everything from wrinkles to slowly stiffening arteries to declines in athletic performance is a consequence of that, and the extreme case when a meaningful percentage of the cells in given organ turning senescent is probably due to either something catastrophic, i.e. infection or an inflammatory diesease, or when you're much older than 40s, i.e. stem cell pools that have run out of divisions.
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