DNA Repair Mechanisms

Genomic instability spurs DNA Repair

Genome instability is defined as higher than normal rates of DNA mutation. Mutation is not necessarily bad, but under the circumstances of today, it is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution.  But as we see today, genomic instability has catastrophic consequences for age-related diseases such as cancer and other chronic diseases as well as accelerated aging.

In terms of causation, mutations arise either from the  molecular inactivation of DNA repair pathways or as a result of an overload of genotoxic stress from cellular processes such as transcription and replication that overwhelm high-fidelity DNA repair. Exposure to external genotoxic agents (pollution) is a huge driver to genomic instability. (Annu Rev Genet. 2013;47:1-32. Source)

“… genome instability can be enhanced by exposure to external genotoxic agents or as the result of cellular pathologies. We review the causes of genome instability as well as how it results in hyper-recombination, genome rearrangements, and chromosome fragmentation and loss, which are mainly mediated by double-strand breaks or single-strand gaps. Such events are primarily associated with defects in DNA replication and the DNA damage response, and show high incidence at repetitive DNA, non-B DNA structures, DNA-protein barriers, and highly transcribed regions. Identifying the causes of genome instability is crucial to understanding genome dynamics during cell proliferation and its role in cancer, aging, and a number of rare genetic diseases.”

A  Nobel Prize in Physiology (Medicine) for DNA repair Discoveries

The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their work on the molecular mechanisms of DNA repair processes. (1) There are two types of DNA repair: nucleotide excision repair and base excision repair. (See Exhibit A below)

DNA Repair

DNA repair is a collection of biochemical processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. (2)

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Top: DNA damage resulting in multiple broken chromosomes (Image C.C.)

Many of these nuclear lesions cause structural damage to the DNA molecule, that which alters or eliminates the cell’s ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell’s genome. These mutations  affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages (interstrand crosslinks or ICLs). Cancer can ensue. (3).

The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states: An irreversible state of dormancy, known as senescence, cell suicide, also known as apoptosis or programmed cell death or unregulated cell division, which can lead to the formation of a tumor that is cancerous.

Repair Genes can also be DNA repair Genes

The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection. (4)

Many of the genes that affect aging and longevity in model organisms, such as mice, fruit flies, and worms, have human homologs (….) These include some of the genes involved in the regulation of DNA repair and nuclear structure, which cause the progeroid syndromes when mutated, as well as those that may affect telomere length, since shorter telomeres have been associated with shorter survival…” (Source)

PARP 1 and DBC 1 Proteins in relation to Aging

 

One of the mechanisms by which the Aging machinery is programmed to block the DNA repair system stems from the latching on to the PARP 1 DNA repair protein by another protein called DBC 1. In the video below, Harvard’s Professor Sinclair explains this phenomenon.

To fix this problem, Professor Sinclear claims that a molecule called Nicotinamide Mononucleotide can “unpop” these two proteins, thanks to which the PARP 1 DNA repair protein can get back to its task of repairing. Is he correct ?

Nicotinamide Adenine Dinucleotide, NMN & DNA Repair

NAD+ is a key co-enzyme and metabolite called Nicotinamide Adenine Dinucleotide (NAD+) that the mitochondria in every cell of human bodies depend on to fuel all basic functions. (Source)  In this perspective, NAD+ plays a key role in communicating between the nucleus of cells and the Mitochondria that power cell activity (Source). One of its key role is to ensure DNA repair, a longevity function which is essential.

“DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate–ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.” (Jun Li, Michael S. Bonkowski, Sébastien Moniot, Dapeng Zhang, Basil P. Hubbard, Alvin J. Y. Ling, Luis A. Rajman, Bo Qin, Zhenkun Lou, Vera Gorbunova, L. Aravind, Clemens Steegborn, David A. Sinclair. A conserved NAD binding pocket that regulates protein-protein interactions during aging. Science, 24 Mar 2017: Vol. 355, Issue 6331, pp. 1312-1317)  (Source) (Full article)

Over time, decreasing NAD+ promotes chronic diseases and aging. (Source). Different scientists claim that decreasing NAD+ is one of the key factors that explains the diabetic epidemic and why we age. (Source) In this perspective, it would appear that the supplement called with Nicotinamide Mononucleotide (NMN), the immediate precursor used by the body to create NAD+, can replenish stores of NAD+ and  help to reverse the aging process via the mechanism mentioned above.

The metabolite NAD+ has a key role as a regulator in protein-to-protein interactions that modulate DNA repair & NMN can help

A recent study showed that treating mice with a NAD+ precursor, or “booster,” called NMN improved their cells’ ability to repair DNA damage caused by radiation exposure or old age. Most recently Professor Sinclair and his team demonstrated that supplying old mice with NMN in their drinking water for 2 months greatly increased the number and size of blood vessels throughout the body, such that they were indistinguishable from young mice. In fact, the old mice who received the supplement had nearly twice the endurance as those that did not, and were as fit and strong as young mice(Source)

In this perspective, a randomized control trial (considered the gold standard of scientific research) from a different group of researchers published in the journal Nature (Nov 2017) a study that showed a substantial, sustained increase in the NAD+ levels over a two-month period of people who took a daily supplement containing NAD+ precursors. Human trials of NMN therapy  are still ongoing. (Source)

Professor Sinclair and his UNSW colleague Dr Lindsay Wu were winners in NASA’s iTech competition in December last year and both claim that this molecule can help to preserve astronauts health from cosmic radiation while also helping 96 per cent of childhood cancer survivors, all of whom suffer a chronic illness by age 45, including cardiovascular disease, Type 2 diabetes, Alzheimer’s disease, and cancers unrelated to the original cancer. Conditins which constitute accelerated aging. “While resveratrol activates SIRT1 alone, NAD+ boosters activate all seven sirtuins, SIRT1-7, and should have an even greater impact on health and longevity,” claims Professor Sinclair. (Source)

Discussion

The evidence does appear to support the claim that when there’s a deficiency of NAD+, there’s a loss of cellular function leading to disease and aging. As well as the claim that supplementation with Nicotinamide Mononucleotide (NMN), the immediate precursor used by the body to create NAD+, can replenish stores of NAD+ and  help to reverse the aging process. The Key issue though lies elsewhere : Is there convinging proof that NMN is better than holistic techniques like exercises, herbology and dietary restriction ? Because if all NMN does is mimick some of holistic lifestyle’s rejuvenation, then this supplement may not be that needed, except maybe for those who refuse to go holistic.

The Anti-aging products from skin creams to chemical peels and sirtuin activators are part of a $250 billion industry, but to my knowledge, not many stand up to medical scrutiny. Sinclair plans to take his NAD+ research through the U.S. Food and Drug Administration (FDA) approval process and eventually create a pill that could be prescribed by a doctor or purchased over the counter.  Another company he is linked with, called Elysium, is already selling a supplement called Basis that contains compounds known to boost NAD+ levels. (Basis is the supplement tested in the 2017 Nature study.) Supplements are not required to undergo years of clinical research and FDA approval processes  Leonard Guarente, Elysium’s chief scientist and co-founder (who also directs the Glenn Center for Biology of Aging Research at MIT where Sinclair works) prudently (from the legal perspective) says Basis is not intended to extend people’s life spans, but only to help them stay healthier for longer. Eight Nobel laureates are on the company’s scientific advisory board. Since Sinclair has sold his resveratrol-based sirtuin (anti-aging enzyme SIRT1 activator) booster company for billions of dollars, just before resveratrol supplements were shown to be not that great of sirtuin-longevity boosters, this NAD team has the funds to pay for the most prestigious Nobel supporters and the most daring scientific and even marketing adventures.

Thus, given the history of this area of metabolism related to sirtuins, caloric restriction mimickers and their manipulation, one has to be prima facie skeptical. Initially promising (and overhyped) results in mice went essentially nowhere, or turned out to make the condition of obesity a little less harmful, while showing little evidence of utility for healthy individuals. If human data showing meaningful benefits from NMN that could not be achieved via exercise or calorie restriction, than ok, this supplement would be interesting. As of now, this supplement appears to be of benefit only to those who prefer to pay rather than exercise or eat less or live holistically. Furthermore, this supplement does not appear to target what is needed in rejuvenation medicine,  techniques to promote the elimination of senescent cells, the repair of DNA and some of the inhibition of other aging pathways that we talked about.

Nicotinamide Riboside & Longevity 

Another NAD+ precursor vitamin is Nicotinamide riboside (NR). NR is a supplement that affects energy generation in mitochondria and gene regulation through the same pathway as resveratrol and caloric restriction.  It has been shown to host NAD+ by over 2 fold with a single dose. It is sold under the label Niagen. A Clinical trial appears to be ongoing. (Source). This one will be recruiting in 2019 (Source)

“Nicotinamide riboside (NR) is in wide use as an NAD+ precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD+ metabolism in humans. We report that human blood NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD+ with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans…” (Source)

Discussion

NR has been promoted since 2014 including via Life Extension. (Source)  At first, when i read about a new life extension supplement that is herald as a “Longevity breakthrough”, like with cancer breakthroughs, my the red lights in my frontal cerebral cortex lighgt up. For example, phrases like “dramatic longevity improvement with fruit flies” , “..we fed it to mice and they lived X% longer”, or better yet, “In preliminary human trials, mortality was found to be ….% lower.” However, as we explained in the Methodology section, all of these phrases must be carefully analyzed to see exactly what the  story is and if the study is not flawed by design.

Looking at the facts in this NR case, it would appear that the articles about NR talk lots about biochemical pathways and chains of genes that promote other genes etc. Biochemistry is important for generating ideas, but we must be wary when the study goes too much into theory and biochemistry. The hard evidence in Longevity medicine remais life extension human trials and epidemiology.  Lab experiments on live mice run hundreds of thousands of dollars to test a single compound.  So its better to test on insects first. Worms and flies are much cheaper to breed than mice, and the experiments last weeks instead of years.  Furthermore, genetics of these lower animals is well-understood, and easy to manipulate. Experiments with worms and flies provide an intermediate proving ground for ideas before the expensive life span trials with rodents.  There are many interventions that work well to extend life in flies that don’t work in mammals. We can’t be testing everything, so we rely on biochemistry for plausible candidates.  But jumping from biochemical theory to marketing of a supplement can be misleading. Going back to NR,  it appears that the evidence for its life expectancy benefit is indirect.  There have been  few positive results for fruit flies, let alone mice.  If it works in humans, benefits will likely be limited to people who are overweight.  And there are reasons to expect only limited benefits from the pathways through which NR works. Furthermore, it may be that there have already been experiments feeding NR to mice or rats, but often, as we saw, negative results don’t get published.

Tentative conclusion: There’s no doubt that Niagen (NR) is capable of boosting NAD+. But the  issue remains that Holistic Lifestyle is also able to accomplish this biochemical feat. Furthermore, all three variations of vitamin B3 are capable of accomplishing the same result, though at different degrees.  Indeed, the evidence appears to indicate that the three variations of vitamin B3, NR, NAM (Nicotinamide), and NA (Nicotinic Acid) are all precursors of NAD+. All three produce NAD+ in the human body. (Cf. Preiss-Handler Pathway, NAD+ Salvage Pathway) Furthermore,  exercise, fasting,  caloric restriction or other techniques can also boost NAD+ at virtually zero monetary cost.We will go into additional details in the Discussion.

 Circadian Rythms Activation & DNA Repair

The aging hallmark relative to the circadian pathway is relatively new. The 2017 Nobel Prize in Physiology (Medicine) went to scientists who dug deep to unravel some of the mysteries of circadian biology. When humans don’t respect Nature’s rhythms like the sleep-wake (melatonin-cortisol) cycle, aging is accelerated.

Deep restorative Sleep is one of Happiness Medicine’s twelve most important wellbeing tools, more powerful than pills, surgery and any high-tech procedure combined, because none of  conventional medicine’s weapons and procedures can repair damaged DNA, spur rejuvenation hormones, charge up neurotransmitters, calm inflammation, calm the mind  and detox beat-up tissues like deep  restorative sleep.

In this Presentation, we  will examine the best deep sleep protocols, including, but not limited to different ways to holistically resolve Apnea, snoring, frequent urination and other sleeping problems. As for holistic ways to promote DNA repair, this topic is so important that we will only briefly talk about it in this Seminar. Seminar B will focus more on this longevity mechanism

Exhibit A

DNA Repair Mechanisms

More on this topic

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Reference and Precision Notes

1.  Broad, William J. (7 October 2015). “Nobel Prize in Chemistry Awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar for DNA Studies”. New York Times. (Source) Staff (7 October 2015). “The Nobel Prize in Chemistry 2015 – DNA repair – providing chemical stability for life” (PDF). Nobel Prize. (Source)

2. Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J (2004). Molecular Biology of the Cell (5th ed.). New York: WH Freeman. p. 963.

3. Charya, PV (1971). “The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides”. Johns Hopkins medical journal. Supplement (1): 254–60. (Source)  And, Bjorksten, J; Acharya, PVN; Ashman, S; Wetlaufer, DB (1971). “Gerogenic fractions in the tritiated rat”. Journal of the American Geriatrics Society. 19 (7): 561–74. (Source).

4. Browner, WS; Kahn, AJ; Ziv, E; Reiner, AP; Oshima, J; Cawthon, RM; Hsueh, WC; Cummings, SR. (2004). “The genetics of human longevity”. Am J Med. 117 (11): 851–60. (Source)

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