15 replies to this topic

[maximum411]

Does anyone know of any compounds that have been proven to reduce DNA damage/mutation?

Off of the top of my head, I can think of chlorophyllin, vanillin, a compound in cinnamon, green tea polyphenols, and sulforaphane (although this has also been shown to induce single-strand breaks, strangely enough).

[Dizzon]

In humans? Blueberries, Oleuropein (olives, olive oil, olive leaf extract), panax (true) ginsing, Siberian Ginsing, Creatine, watercress, curcumin (& piperine), Lemon Balm, Garlic.

Blueberries and Olive leaf extract seem to be the most potent at preventing/reducing DNA damage.

Edited by Dizzon, 15 November 2013 - 04:58 PM.

[zorba990]

Kiwi
http://www.ncbi.nlm....pubmed/12663512

Carcinogenesis. 2003 Mar;24(3):511-5.
Nutritional modulation of DNA repair in a human intervention study.

Collins AR, Harrington V, Drew J, Melvin R.

Source

Institute for Nutrition Research, University of Oslo, POB 1046 Blindern, N-0316 Oslo, Norway. a.r.collins@basalmed.uio.no

Abstract


DNA oxidation is a potential cause of cancer in humans. It is well-known that fruits and vegetables protect against cancer, and this may be in part because they contain antioxidants, which decrease the level of oxidation of DNA. However, there are other possible mechanisms, such as an enhancement of cellular repair of this damage. A randomized cross-over study was carried out on healthy human subjects, who were given kiwifruit as a supplement to their normal diet, for 3-week periods at different 'doses', with 2-week washout periods between doses. Endogenous oxidation of bases in lymphocyte DNA, and the resistance of the DNA to oxidation ex vivo, were assessed using single cell gel electrophoresis (the 'comet assay'). The capacity to repair DNA base oxidation was measured with an in vitro test, and levels of expression of repair-related genes OGG1 and APE1 were assessed by semi-quantitative RT-PCR. Concentrations of dietary antioxidants were measured in plasma. The antioxidant status of plasma and of lymphocytes was increased by consumption of kiwifruit. Levels of endogenous oxidation of pyrimidines and purines in DNA were markedly decreased, and DNA repair measured on a substrate containing 8-oxo-7,8-dihydroguanine was substantially increased (without change in levels of OGG1 or APE1 mRNA). The magnitude of these effects was generally not related to the number of kiwifruits consumed per day. Kiwifruit provides a dual protection against oxidative DNA damage, enhancing antioxidant levels and stimulating DNA repair. It is probable that together these effects would decrease the risk of mutagenic changes leading to cancer.

[Dizzon]

Cant believe I forgot Kiwi!

Also Green (and potentially White and Oolong but not Black) Tea and Broccoli (and probably most other non-bok choy cruciferous vegetables)
http://www.ncbi.nlm....pubmed/14519830
http://www.ncbi.nlm....pubmed/20713433

Would have posted links for the previously mentioned supplements but it would have taken a bit too long to do all of them

[blood]

Aspirin!

http://www.ucsf.edu/...wing-dna-damage

http://www.plosgenet...al.pgen.1003553

[zorba990]

k2, d
http://articles.merc...vitamin-k2.aspx
melatonin, epitalon, anything that helps pineal function

Lipopolysaccharide-induced DNA damage is greatly reduced in rats treated with the pineal hormone melatonin

http://www.sciencedi...30372079503742X

http://www.super-nut...pplements--H644

http://books.google....ved=0CDMQ6AEwBA

Edited by zorba990, 16 November 2013 - 08:46 PM.

[Logic]

GDF11: (???)
http://www.bioscienc...hit-clinic-year

Niacin and/or Nicotinamide Riboside but NOT Nicotinamide/niacinimide via PARP:
http://www.longecity...ndpost&p=634256

Selenium, selenomethionine
Uncaria tomentosa (downtregulates WNT signalling in canceronly? not good for longevity)
Ubiquitin
Interleukin-12
Polypodium leucotomos
http://www.drpasswat.../dnarepair.html
http://escholarship....c/item/9ww9f65d

"...A recent study by Niture, et al., reports an increase in MGMT expression by use of cysteine/glutathione enhancing drugs and natural antioxidants...
...Mice with a point mutation in both copies of the Pold1 gene demonstrated a loss of proofreading activity by DNA polymerase-δ and developed epithelial cancers at a significantly higher rate than did mice with wild-type genes...
...A group of proteins known as mismatch excision repair (MMR) enzymes is capable of correcting errors of replication not detected by the proofreading activities of DNA polymerase...Mutations in the human mismatch excision repair genes MSH2 and MLH1 are associated with hereditary non-polyposis colorectal cancer..."
http://www.sigmaaldr...and-repair.html

DNA Repair Enzymes (may be orally bioavailable in a liposomal formulation???)
https://www.neb.com/...-repair-enzymes
http://www.rndsystem...airenzymes.aspx
http://www.foxnews.c...cer-treatments/

DNA Repair and Cancer Therapy: Targeting APE1/Ref-1 Using Dietary Agents
http://www.hindawi.c...jo/2012/370481/
 

[niner]

DNA Repair Enzymes (may be orally bioavailable in a liposomal formulation???)

 

Odds are very slim.  It would need to be delivered, intact and functional, into the nucleus.   Nuclear DNA mutation is not a big contributor to aging, according to SENS, although if it leads to cancer that's a different story.

[Logic]

Thx Niner.
I got the idea from somewhere that was talking about skin creams and said they were delivered to the nucleus in skin?
Also liposomal C, Curcumin, etc. seem to be popular?

I am aware of SENS's viewpoint but feel that avoiding damage with a well researched supplement stack is good insrance against SENS being wrong.

 

 

Some arguments to the contrary:

DNA Damage, Aging, and Cancer
This review gives an account of how the cell repairs DNA damage and presents evidence that DNA damage contributes to aging and cancer, with the outcome dependent on the type and number of lesions in DNA
http://www.nejm.org/...6/NEJMra0804615

DNA damage checkpoints in stem cells, ageing and cancer
DNA damage induces cell-intrinsic checkpoints, including p53 and retinoblastoma (RB), as well as upstream regulators (exonuclease 1 (EXO1), ataxia telangiectasia mutated (ATM), ATR, p16INK4a and p19ARF) and downstream targets (p21, PUMA (p53 upregulated modulator of apoptosis) and sestrins). Clearance of damaged cells by cell-intrinsic checkpoints suppresses carcinogenesis but as a downside may impair stem cell and tissue maintenance during ageing. Modulating the activity of DNA damage checkpoints can either accelerate or decelerate tissue ageing and age-related carcinogenesis. The outcome depends on cell-intrinsic and cell-extrinsic mechanisms that regulate the clearance of damaged cells and on the molecular context in ageing tissues, including the level of DNA damage accumulation itself.
http://www.nature.co...ll/nrm3420.html

Cancer and Aging as Consequences of Un-Repaired DNA Damage
https://www.novapubl...oducts_id=43247

[maximum411]

Thank you Logic! I had read about Uncaria tomentosa (cat's claw) reducing DNA damage accumulation before, and actually take it as a supplement. Could you explain what you mean about Wnt signaling and it not being good for longevity?

Also, I have no idea where SENS adopted the viewpoint that nuclear DNA damage is not an important part of the aging process. There is an enormous body of experimental evidence indicating that it is. Even if is only important in the context of cancer (which it is not), cancer is a major part of the aging process, and its incidence increases drastically with age. Eventually, every person's mutation load will accumulate to the point where they develop cancer unless they die of something else first. Simply developing better ways to remove tumors will not be the final answer to the problem of cancer, because even non-tumorous cells harbor pre-cancerous mutations, and they do so at higher rates the older you get. The only way to truly prevent cancer is to prevent mutation.

Frankly, I think the only reason SENS takes this viewpoint is because there is no quick-fix solution to the problem of mutation, barring human genetic modification for improved DNA repair efficacy. I have nothing against SENS, but I think their ideology can get in the way of their science sometimes.

[maximum411]

Oh, and I assume the skin cream you are talking about is T4 endonuclease lotion. They did actually have success in delivering bacterial DNA repair enzymes into skin cells through liposomal encapsulation, and were able to improve DNA repair efficacy. Dr. Daniel Yarosh actually moved the cream into clinical trials as a treatment for xeroderma pigmentosum, and saw efficacy, but failed to gain FDA approval mainly because their small sample size was deemed not convincing enough.

[Logic]

Thank you Logic! I had read about Uncaria tomentosa (cat's claw) reducing DNA damage accumulation before, and actually take it as a supplement. Could you explain what you mean about Wnt signaling and it not being good for longevity?

That is a very good question maximum411.
One I was actually asking myself and forgot to edit as you can see from the terrible grammar/spelling.

I recalled  WNT signalling from this thread:
http://www.longecity...osteoarthritis/

I am now in the process of researching it and have to admit to complete confusion at this point as some studies point to increased longevity, while other point to a decrease!?
 

Phytosubstances – focus on cat’s claw
http://www.anti-agin...2011/09/29/702/

Note that Cat's Claw was only tested on cancer cells in this study and that substances like this and resveratrol etc quite often have quite different effects in healthy cells where they do good things for longevity.
The study goes on to say: "...Downregulation of Wnt-signaling by a dominant negative-TCF-4 variant in non-cancer cells rendered the cells insensitive towards treatment with B/S(rt). B/Srt was less toxic in non-cancer cells than in cancer cells..."
Note that this was NOT caused by Cat's Claw but by a dominant negative-TCF-4 variant???
 

Curcumin, cancer and longevity
http://www.anti-agin...-and-longevity/

"...Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 microM and completely at 10 microM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 microM and completely at 10 microM..."
 
Note that Curcumin is known to be neuroprotective and cause neurogenesis:
http://www.anti-agin...-and-longevity/


The Nuclear DNA Damage/Mutation Theory of Aging
http://www.anti-agin...heory-of-aging/

"...Additionally, senescent cells may alter stem cell proliferation by competing for soluble small molecules such as members of the Transforming Growth Factor-β (TGF- β)and Wnt families, as is seen in drosophila models (see ref 5). Additional evidence comes from the fact that, “In mammals, circulating levels of Wnt signal proteins increase with age, and this increase triggers muscle stem-cell ageing..."
 
(This whole post is pertinent to the thread topic and worth reading)


Jim Watson’s “Top 12” List of “Things I Learned about Aging” in 2013
http://www.anti-agin...-aging-in-2013/

"...while cancer biologist have mainly focused on the Wnt signaling pathway as the primary “early driver” of cancer. there is something else going on too.. Wnt drives β-catenin into the nucleus where it activates the transcription factor TCF to “turn on” the EMT. Watson believes an “even more important villain than Wnt signaling has been virtually staring us in the face for two decades”. That “villain” is interleukin 6 (IL-6). IL-6 is the master cytokine mediator of inflammation and immunity. Recently, IL-6 has also been found to be the principle biomarker for cellular senescence. Specifically, senescent cells secrete the senescence associated secretory phenotype (SASP), which is a group of over 70 cytokines secreted by senescent cells. This explains why the two phenomena, aging and cancer, are chronologically linked. IL-6 can generate paracrine and autocrine feedback loops, thereby activating nearby cells to become cancerous and self-activating the production of more IL-6. This in turn induces apoptosis-resistance by blocking genes required for programmed cell death..."

 

Age-related cognitive decline: focus on interventions
http://www.anti-agin...-interventions/

“Here, we show that both the levels of Wnt3 protein and the number of Wnt3-secreting astrocytes influence the impairment of adult neurogenesis during aging. The age-associated reduction in Wnt3 levels affects the regulation of target genes..."


ACE and Angiotensin II: The “Double Agents” that Play Multiple Roles in the Molecular Story of Life
http://www.anti-agin...-story-of-life/
"...◾For example, many solid cancers, including colon, have recently been shown to be initiated by Wnt, which acts upstream of beta-catenin and APC.
◾Wnt is activated by PKC, which is activated by Angiotensin II.
◾Thus, Angiotensin II production by vascular endothelial cells (sACE) is an "up stream" cause of increased Wnt signaling..."

 
I suspect the answer lies in following these 'streams', but have run out of time to do so atm.

Perhaps someone else has some answers?

[Dorian Grey]

IP6 appears to have a positive effect on DNA repair in the test tube...  I'm doing a one man in vivo study (on) myself.  

 

http://www.ncbi.nlm....pubmed/11030616

 

Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair

 

Abstract

In mammalian cells, double-strand breaks in DNA can be repaired by nonhomologous end-joining (NHEJ), a process dependent upon Ku70/80, DNA-PKcs, XRCC4, and DNA ligase IV. Starting with HeLa cell-free extracts, which promote NHEJ in a reaction dependent upon all of these proteins, we have purified a novel factor that stimulates DNA end-joining in vitro. Using a combination of phosphorus NMR, mass spectroscopy, and strong anion exchange chromatography, we identify this factor as inositol hexakisphosphate (IP6). Purified IP6 is bound by DNA-PK and specifically stimulates DNA-PK-dependent end-joining in vitro. The involvement of inositol phosphate in DNA-PK-dependent NHEJ is of particular interest since the catalytic domain of DNA-PKcs is similar to that found in the phosphatidylinositol 3 (PI 3)-kinase family.

PMID: 11030616

 

Edited by synesthesia, 04 September 2014 - 01:50 AM.

[maximum411]

One issue I see with this is that non-homologous end joining is highly mutagenic, and an inferior way to repair DNA stand breaks in comparison to homologous recombination.

[Dorian Grey]

Interesting red flag Max...  

 

Haven't dug into this too deeply yet, but this blurb on Wikipedia (for what it's worth) seems to indicate though non-homologous repair can result in errors, the alternative method may be more dangerous still.  

 

http://en.wikipedia....ous_end_joining

 

"NHEJ is evolutionarily conserved throughout all kingdoms of life and is the predominant double-strand break repair pathway in mammalian cells"

 

"When the NHEJ pathway is inactivated, double-strand breaks can be repaired by a more error-prone pathway called microhomology-mediated end joining (MMEJ)"

 

This page ( http://en.wikipedia....s_recombination ) seems to state homologous repair only occurs during DNA replication/mitosis and NHEJ is the predominant form of repair throughout the bulk of the life of the cell?  (scroll to: Timing within the mitotic cell cycle)

 

"Homologous recombination repairs DNA before the cell enters mitosis (M phase). It occurs during and shortly after DNA replication"

 

" NHEJ is predominant in the G₁ phase of the cell cycle, when the cell is growing but not yet ready to divide. It occurs less frequently after the G₁phase, but maintains at least some activity throughout the cell cycle. The mechanisms that regulate homologous recombination and NHEJ throughout the cell cycle vary widely between species"

 

This seems to indicate homologous repair (only?) occurs when errors hapen during the DNA replication phase of mitosis, and DNA damage after mitosis (normal wear and tear) is always repaired via NHEJ or the more error prone MMEJ?

 

I'd be interested in any good info you might have on this.  

 

Thanks for your input.  

Edited by synesthesia, 05 September 2014 - 12:32 AM.

[Logic]

Nuclear DNA damage signalling to mitochondria in ageing

Mitochondrial dysfunction is a hallmark of ageing, and mitochondrial maintenance may lead to increased healthspan. Emerging evidence suggests a crucial role for signalling from the nucleus to mitochondria (NM signalling) in regulating mitochondrial function and ageing. An important initiator of NM signalling is nuclear DNA damage, which accumulates with age and may contribute to the development of age-associated diseases. DNA damage-dependent NM signalling constitutes a network that includes nuclear sirtuins and controls genomic stability and mitochondrial integrity. Pharmacological modulation of NM signalling is a promising novel approach for the prevention and treatment of age-associated diseases.

http://www.nature.co...rm.2016.14.html