16 replies to this topic

[Ovidus]

In my opinion, this hypothesis is tremendously important and brings together a number of crucial elements in the field. Yet, it may be too simple for most people to seriously think about it.

 

You maybe familiar with Line-1: this is a part of our genome that is purely junk. Line-1 is repeated over and over and over again in our genome but serves us no useful function. It is there so many times, because it is a transposable element. It is a virus-like structure that has gained the ability to make copies of itself and insert these copies into our genome. It is pretty crazy when you think about it. 17% of our genome consists of this repeating pattern called Line-1.

 

Back in he day, people used to think that Lne-1 was just useless, but it now turns out that it may be extremely harmful. The repeated self-copying and reinsertion of this piece of DNA fragment may wreak havoc on the genome and cause both aging and cancer. 
Have you guys listed to some of the David Sinclair interviews where he says "aging occurs not because our genome base pairs get degraded and information is lost. Instead, aging occurs when the expression of genes begins to occur in non-ideal fashion and some elements in the genome that need to be expressed are not, while others that need to be suppressed begin to be expressed" (not his exact words, my rephrasing of his comments, based on my recollection)

 

Well these two researchers say the same thing here:

https://www.youtube....GIyfn6SI&t=904s

 

https://www.youtube....ABgkm-w&t=1514s

 

However, they go a step further and specify what exactly it is that gets overexpressed in aging. 

They say that Line-1 needs to be suppressed and while we are healthy and young Sirtuins do exactly this. (Sinclair also says that Sirtuins are expressed when we are young -when Sirtuin expression stops we get in trouble he claims). When Sirtuin expression stops (or goes down significantly) Line-1 gets our of control and starts making tons of copies of itself and inserts those copies into the genome. It is greedy and instead of occupying just 17% of the genome, you can think of it as wanting to take over the entire genome. 

The crucial part is that there is an enzyme used during this process: REVERSE TRANSCRIPTASE. The same enzyme is used by the HIV Virus, while it makes copies of itself and inserts those copies into our genome. Hence, some AIDS drugs can work -and seem to work very well- as a cure to aging. They work, because they prevent Line-1 from inserting itself into the genome. 

 

AIDS drugs do have side effects, yes. But inhibiting REVERSE TRANSCRIPTASE does not sound like a deadly intervention. It could work well actually (more on what exact side effects this may involve is to be discussed a little later -let us first understand if its suppression would yield any real benefits at all) 

Please watch and comment if you can. This is important ladies and gentlemen..... 

 

 

 

 

[Turnbuckle]

"aging occurs not because our genome base pairs get degraded and information is lost. Instead, aging occurs when the expression of genes begins to occur in non-ideal fashion and some elements in the genome that need to be expressed are not, while others that need to be suppressed begin to be expressed"

 

 

 

That's what happens with epigenetic aging. Epigenetic mutations occur at a rate much higher than that of the underlying DNA, detuning protein production. There are some 200 cell types in the human body, and they are distinguished only by their epigenetic coding. Scramble that coding and the entire system breaks down. Fortunately, you can get rid of old cells with scrambled coding, and the body does this naturally by using telomere shortening as an expiration date, which when reached stimulates senescence, and then apoptosis. Unfortunately, the process of removal lags with time even as the stem cell pools that supply new cells dry up.

 

Subsets of this epigenetic scrambling correlate extremely well with chronological aging, and can be use as a clock. Horvath's clock, for instance.

Using a weighted average of DNA methylation, the Horvath clock can return an incredibly accurate reading of chronological age. Recent versions of the clock have been able to accurately predict mortality. Which is to say, Horvath’s clock can figure out roughly when yours will stop ticking.

https://endpoints.el...ng-7a6d3a94d2e4

 

 

 

As for the junk status of cells, humans seem to have an average amount, and no one has yet shown that junk does anything in regard to aging. Removal of millions of base pairs in mice did nothing, apparently.

 

Edward Rubin's team at the Lawrence Berkeley National Laboratory in California has shown that deleting large sections of non-coding DNA from mice appears not to affect their development, longevity or reproduction.

 

https://www.nature.c...l/041018-7.html

 

 

 

 

Edited by Turnbuckle, 22 August 2019 - 09:39 AM.

[Ovidus]

 

 

 

As for the junk status of cells, humans seem to have an average amount, and no one has yet shown that junk does anything in regard to aging. Removal of millions of base pairs in mice did nothing, apparently.

 

"Edward Rubin's team at the Lawrence Berkeley National Laboratory in California has shown that deleting large sections of non-coding DNA from mice appears not to affect their development, longevity or reproduction.

 

https://www.nature.c...l/041018-7.html"

 

 

Thanks a lot Turnbuckle.

 

So, in the experiment above, researchers removed all of Line-1 (Line-1 does not code for anything; it is non-coding section of the DNA) and that did not alter lifespan. Hence, we can say that silencing Line-1's self replicating activity is not likely to alter aging. Do I understand that accurately?

[smithx]

Thanks a lot Turnbuckle.

 

So, in the experiment above, researchers removed all of Line-1 (Line-1 does not code for anything; it is non-coding section of the DNA) and that did not alter lifespan. Hence, we can say that silencing Line-1's self replicating activity is not likely to alter aging. Do I understand that accurately?

 

This is incorrect. LINE1 is not non-coding. It codes for an endogenous retrovirus reverse transcriptase which is now known to start causing DNA damage with age, and to precipitate cellular senescence, among other things. It also comprises about 18% of our total set of DNA. It's being found to be implicated in everything from osteoarthritis to cancer (see here, for example: https://www.oarsijou...0418-6/fulltext - they don't make the connection to LINE1, but do mention that reduced SIRT6 is found in the cartilage of osteoarthritis sufferers who have more senescent cells).

 

LINE1 is normally inhibited from being expressed by the SIRT6, which is NAD dependent and which has an affinity for histones and telomeres, among other things. With age, there is less SIRT6, so at some point the LINE1 reverse transcriptase starts being expressed and starts causing damage and inducing senescence.

 

It is likely but I haven't yet found evidence yet, that lack of NAD+ could be implicated at least partially in the decreased levels of SIRT6, so supplementing with NDA+ precursors could help.

 

Other things which have been found to be useful are plant polyphenols: https://www.nature.c...598-018-22388-5 of which the most powerful tested was cyanidin - found in various red and purple fruits and vegetables: https://en.wikipedia.../wiki/Cyanidin. This is also interesting https://www.ncbi.nlm...pubmed/21121259

 

SIRT6 prevents expression of LINE1 reverse transcriptase (sometimes called "transposons) -- once expressed it can be inhibited by drugs like Lamivudine. The same dosages (or perhaps half of the usual dose) prescribed for Hep B should almost totally inhibit this destructive agent.

 

There are other good reasons to keep levels of SIRT6 high, however, besides the fact that it's probably better to avoid expression of this dangerous agent rather than trying to inactivate it post-facto: SIRT6 also seems to be protective of telomeres and has other beneficial functions. I can supply some references later.

 

 

The fun thing about this all (or the sad thing, since I never published it) is that it's very similar to my original hypothesis of aging from the early 70s which was that "inactive state viruses" as they were called then, were responsible for aging because we were descended from the survivors of ancient pandemics who were resistant enough to live long enough to procreate and raise the children, but not entirely resistant. From then until recently there was very little if any evidence that this could be the case, but now it seems that endogenous retroviruses (which were unknown back then) actually are one of the major causes of aging or at least of setting a fairly hard limit on maximum lifespan.

 

 

 

 

Edited by smithx, 03 September 2019 - 02:56 AM.

[Ovidus]

Thank you so much Smithx

 

Definitely agree with your points. 

Some people may object to your statement that "This is incorrect. LINE1 is not non-coding. It codes for an endogenous retrovirus reverse transcriptase..." by saying that LINE1 does not code for any proteins that are essential to the functioning of the mamalian metabolism -i.e. LINE1 is selfish and only codes for stuff that it needs; not for stuff that we need.

Again, even if so, I agree with your premise. 

Earlier Turnbuckle referenced a link where it said:
"Edward Rubin's team at the Lawrence Berkeley National Laboratory in California has shown that deleting large sections of non-coding DNA from mice appears not to affect their development, longevity or reproduction."

However, this is a tremendously misleading statement. 

Read the link and it says: "The team created mice with more than a million base pairs of non-coding DNA missing - equivalent to about 1% of their genome." So.... the researcjers DEFINITELY DID NOT REMOVE LINE1 from the mouse genome. LINE 1 makes up 17 to 20 percent of mamalian DNA depending on what source you read. They removed just 1 percent of DNA; and it is very likely that this 1 percent was not purely LINE1.

 

 

The big question is this: 
Can we just completely SUPPRESS ALL REVERSE TRANSCRIPTASE ACTIVITY? Do we need some reverse transcriptase?

 

Only useful function of reverse transcriptase is when telomerase is active and it lengthens telomeres by inserting copies of telomere sequences into the genome through the use of Reverse Transcriptase. However, adults do not express any telomerase anyways. 

In fact, telomerase gets expressed in adult humans mostly during cancer (AFAIK, something like 90% of cancers need telomerase to function).
So could it be that we can whack both cancer and aging over the head by inhibiting reverse transcriptase?

 

Thanks a ton
 

 

"Edward Rubin's team at the Lawrence Berkeley National Laboratory in California has shown that deleting large sections of non-coding DNA from mice appears not to affect their development, longevity or reproduction.

[smithx]

With regard to what LINE-1 codes for, one reference is this interesting paper:

 

Inhibition of LINE-1 Retrotransposition by Capsaicin

https://www.mdpi.com...1-ijms-19-03243

 

The eukaryotic genome contains retrotransposable elements, also known as retrotransposons, with or without long terminal repeats (LTRs). Long interspersed nuclear element 1 (LINE-1 or L1) is a non-LTR retrotransposon and constitutes approximately 17% of the human genome [1]. L1 consists of a 5′ untranslated region (UTR), two open reading frames (ORFs) that encode two proteins, ORF1p and ORF2p, and a 3′ UTR with a polyadenylation signal. ORF1p is an RNA-binding protein with nucleic acid chaperone activity that is required for L1 retrotransposition [2]. ORF2p is a protein with endonuclease and reverse transcriptase (RT) activity responsible for a “copy-and-paste” retrotransposition of L1s to new genomic loci [3,4]. Although most L1s are truncated and therefore defective for retrotransposition activity, approximately 100 copies are still competent [3,4].

 

 

 

 

Edited by smithx, 03 September 2019 - 04:55 PM.

[Ovidus]

With regard to what LINE-1 codes for, one reference is this interesting paper:

 

Inhibition of LINE-1 Retrotransposition by Capsaicin

https://www.mdpi.com...1-ijms-19-03243

Damn that's impressive

If you look at the graph, sufficiently high doses of Capsaicin very very severely suppress LINE1 activity.

Can we achieve such high concentrations with oral capsaicin consumption at all?

[William Sterog]

Capsaicin containing foods may be neurotoxic. I don't now if they directly impact the brain, or if the effect is just mediated by a disruption of the gut lining.

https://www.ncbi.nlm...les/PMC6566199/

But it doesn't look good.

17. Chard P.S., Bleakman D., Savidge J.R., Miller R.J. Capsaicin-induced neurotoxicity in cultured dorsal root ganglion neurons: Involvement of calcium-activated proteases. Neuroscience. 1995;65:1099–1108. doi: 10.1016/0306-4522(94)00548-J. [PubMed] [CrossRef] [Google Scholar]

18. Jancso G., Kiraly E., Such G., Joo F., Nagy A. Neurotoxic effect of capsaicin in mammals. Acta Physiol. Hung. 1987;69:295–313. [PubMed] [Google Scholar]

Doesn't look good at all.

Using chili intake as a continuous variable, in the fully adjusted model (model 5), for each 10 g increase of chili intake, the beta coefficient for the global cognitive score was −0.13 (95%CI −0.20, −0.07) (p < 0.001).

Edited by William Sterog, 04 September 2019 - 07:45 AM.

[Turnbuckle]

If line-1 causes aging, what about animals that lack line-1 activity? The following paper looked into one group of bats that lacks it--

 

It is difficult to prove that there has been complete loss of L1 activity in any mammalian species rather than a precipitous decline in activity, but three independent lines of inquiry contain multiple indicators that support L1 extinction in all megabat species studied here. 

https://www.genetics...78/1/393#ref-49

 

 

Megabats are large fruit bats that live 15-20 years in the wild. This is typical for bats, which can live 4 times as long as similarly sized mammals. Though line-1 may not make the difference in longevity, bats as a group are long lived--

 

Only 19 mammal species live proportionately longer than humans given their body size, and 18 are bats (17), with Brandt’s bat (Myotis brandtii ) holding the reported record for bat longevity [>41 years, ∼7 g (18)].

https://www.annualre...l-022516-022811

 

 

 

Bats like birds have relatively smaller genomes. They average 2.0 Gb, while birds range from .9 to 1.3 Gb. By comparison, humans have 2.9 Gb, mice 2.5 Gb, elephants 4.0 Gb, and amoebas 670 Gb. (An amoeba either lives 2 days or is immortal, depending on how you define lifespan.)

 

 

 

Edited by Turnbuckle, 04 September 2019 - 10:35 AM.

[smithx]

 

If line-1 causes aging, what about animals that lack line-1 activity? The following paper looked into one group of bats that lacks it--

 

 

Megabats are large fruit bats that live 15-20 years in the wild. This is typical for bats, which can live 4 times as long as similarly sized mammals. Though line-1 may not make the difference in longevity, bats as a group are long lived--

 

This is good information, but I was not quickly able to find information on the lifespan of the particular bat studied, Peropteryx macrotis. It is true that megabats in general live up to 30 years in captivity, but there doesn't seem to be good data on that one:

 

https://animaldivers...teryx_macrotis/

 

Lifespan/Longevity
Information about the lifespan of Peropteryx macrotis is unavailable.

 

I don't think that L1 reverse transcriptases are the single cause of aging, however it may be a major cause both cellular senescence and of the rapid acceleration of aging past a certain point, and may also be the cause or one of the major causes of the "hard limit" of lifespan at least in humans.

 

 

Edited by smithx, 04 September 2019 - 05:49 PM.

[sub7]

Bats are notorious for living long

 

https://arstechnica....long-lifespans/

 

they are definitely one of the longevity heroes 

 

Now one would need to do a cross-bat analysis to see the correlation of LINE1 (lack thereof) activity and lifespan and see the relationship within the bat population

That'd give a better idea of the relative contribution of LINE1 activity to lifespan amongst bats.

 

However, at first glance it looks like the ridiculously long lifespan of bats supports the LINE1 hypotheses...

[Ovidus]

Capsaicin containing foods may be neurotoxic. I don't now if they directly impact the brain, or if the effect is just mediated by a disruption of the gut lining.
 

 How about pure Capsaicin? Is that also toxic? Or are the other constituents of Capsaicin containing foods besides the Capsaicin itself that are toxic? 

[Ovidus]

Capsaicin containing foods may be neurotoxic. I don't now if they directly impact the brain, or if the effect is just mediated by a disruption of the gut lining.
 

 

is it just the whole foods containing Capsaicin that are toxic?
Or is pure capsaicin also toxic (if such a thing can be bought at all -checking the supplements and not sure if any are pure, pure Capsaicin)

[Turnbuckle]

This paper proposes that L1 can become toxic after a threshold is reached, and suggests L1 expression is involved in certain neural diseases like Parkinson's--

 

LINE-1 repression attenuates degeneration in adult dopaminergic neurons

 

The analysis of L1 expression in different structures demonstrates a basal,

thus physiological, level of expression in all regions examined. It can thus be

proposed that L1 expression becomes toxic only after a given threshold has been

reached due to an endogenous (e.g. oxidative) or environmental (e.g. toxic agent)

stress. 

https://www.biorxiv....164608.full.pdf

 

Certain drugs can unsilence L1, such as cocaine--

 

Cocaine-mediated decreases in H3K9me3 enrichment at specific genomic repeats [e.g., long interspersed nuclear element (LINE)-1 repeats] were further confirmed by the increased expression of LINE-1 retrotransposon-associated repetitive elements in NAc. Such increases likely reflect global patterns of genomic destabilization in this brain region after repeated cocaine administration and open the door for future investigations into the epigenetic and genetic basis of drug addiction.

https://www.ncbi.nlm...les/PMC3041122/

 

 

Edited by Turnbuckle, 05 September 2019 - 10:52 AM.

[William Sterog]

is it just the whole foods containing Capsaicin that are toxic?
Or is pure capsaicin also toxic (if such a thing can be bought at all -checking the supplements and not sure if any are pure, pure Capsaicin)

The paper I pasted speculates that it is capsaicin itself the neurotoxic compound.

[ta5]

The paper I pasted speculates that it is capsaicin itself the neurotoxic compound.

 

Wow, this sucks. I consumed gallons of hot sauce over the decades. I estimate about two gallons per year for the last 25 years. 

[William Sterog]

Wow, this sucks. I consumed gallons of hot sauce over the decades. I estimate about two gallons per year for the last 25 years.

I have been putting cayennes in everything for years...

Edited by William Sterog, 06 September 2019 - 08:42 AM.