This article was originally published in Cryonics Magazine, 2011 Issue #1

I am an ardent supporter of Dr. Aubrey de Grey and his work to advance rejuvenation science. The man is priceless and unique in his concepts, brilliance, dedication, organizational abilities, and networking skill. His impact on anti-aging science has been powerful. I have attended all four of the conferences he has organized at Cambridge University in England. For the February 2006 issue of LIFE EXTENSION magazine I interviewed Dr. de Grey, and for the December 2007 issue of LIFE EXTENSION I wrote a review of ENDING AGING, the book he co-authored with Michael Rae.

Dr. de Grey asserts that aging is the result of seven kinds of damage – and that technologies that repair all seven types of damage will result in rejuvenation. His seven-fold program for damage repair is called SENS: “Strategies for Engineered Negligible Senescence”. Dr. de Grey asserts that repairing aging damage is a more effective approach than attempting to slow or prevent aging, and I agree with him. Being an ardent supporter of SENS has not stopped me from simultaneously being a critic of aspects of his program that I think are flawed or deficient. I will attempt to outline some of my criticisms in simple language, assuming that my readers have some knowledge of basic science.

Two SENS strategies cannot justly be described as damage-repair, in my opinion. To protect mitochondrial DNA from free radical damage he wants to make copies of mitochondrial DNA in the nucleus – and import the resulting proteins back into the mitochondria. I would call this an attempt to slow or prevent aging – it cannot be called repair.

Similarly, SENS aims to eliminate cancer by deletion of genes that contribute to cancer, specifically telomerase and ALT (Alternate Lengthening of Telomeres) genes. I am not convinced that this is the best way to eliminate cancer, and I do not believe that deleting cancer-producing genes can properly be called damage-repair.

My criticisms about a procrustean attempt to force two strategies into a model purporting to only be concerned with damage and repair is minor, however, compared to a more fundamental concern that I have that a significant form of aging damage may be being ignored by SENS. I have written a review expressing my concern entitled “Nuclear DNA Damage as a Direct Cause of Aging” that was published in the June 2009 issue of the peer-reviewed journal Rejuvenation Research, [note 1] a journal of which Dr. de Grey is Editor-in-Chief. A PDF of my review is available in the life extension section of my website BENBEST.COM. Those interested in all the citations for claims I will make in this essay are encouraged to read my review. In this essay, I limit my citations to only a few critical articles.

There are many types of DNA damage, but for the purposes of this essay I will focus on breakage of both DNA strands – resulting in a gap in a chromosome. There are two mechanisms for repairing double-strand DNA breaks: Homologous Recombination (HR) and Non-Homologous End-Joining (NHEJ). HR usually results in perfect repair, but HR can only operate when cells are dividing. NHEJ is the more frequent form of double-strand break repair, but it is error-prone. NHEJ is the only DNA repair mechanism available for non-dividing cells. Even in cells that divide, 75% of double-strand breaks are repaired by NHEJ. [note 2]

It is hard to believe that it could be a coincidence that the most notorious “accelerated aging” diseases are due to defective DNA repair. The two most prominent of these diseases are Werner’s syndrome (“adult progeria”) and Hutchinson-Gilford syndrome (“childhood progeria”), both of which are caused by defective nuclear DNA repair, mainly HR. In both diseases the “aging phenotype” is apparently due to high levels of apoptosis and cellular senescence. Apoptosis (“cell suicide”) and cellular senescence (cessation of cell division) are both mechanisms that are induced in cells experiencing nuclear DNA damage that the cell is unable to repair. It is not surprising that victims suffering massive depletion of properly functioning cells should exhibit “accelerated aging”. Mice that are genetically altered to show increased apoptosis and cellular senescence also show an “accelerated aging phenotype”.

Elimination of senescent cells and stem-cell replenishment of cells depleted in tissues by this elimination – as well as depleted by apoptosis – are part of SENS. But these strategies are only applicable to cells that divide – not to non-dividing cells such as neurons. Cryonicists are acutely aware that organs – and even whole bodies – can be replaced, but brains (neurons, axons, dendrites, and synapses, particularly) must be preserved if we are not to lose memory and personal identity. The ability of future medicine to replace all organs and tissues other than the brain would render most of SENS unnecessary – except for the brain.

There is considerable evidence of a significant role for DNA damage in brain aging. There are nearly twice as many double-stand nuclear DNA breaks in the cerebral cortex of adult (180 days) rats as in young rats (4 days) – and old (over 780 days) rats have more than twice the double-strand breaks as adult rats. [note 3] Adult rats show a 28% decrease in NHEJ activity in the cerebral cortex neurons compared to neonatal rats – and old rats show a 40% decrease. [note 4] Declining NHEJ activity with age is at least partially due to ATP decline and cellular damage that SENS is intended to fix. But even if NHEJ activity did not decline with age, nuclear DNA damage in neurons will increase at least in part because NHEJ is so error-prone.

Nuclear DNA damage typically leads to mutation or DNA repair – or apoptosis or cellular senescence when DNA repair fails (a mechanism that is believed to have evolved for protection against cancer). But not all DNA damage is repaired, and NHEJ repair is often defective. Accumulating DNA damage and mutation can lead to increasingly dysfunctional cells.

Cancer is due to nuclear DNA damage, mutations, and epimutations. Dr. de Grey has written that “only cancer matters” for mutation and epimutation to nuclear DNA. His mutation terminology does not even acknowledge DNA damage. He has assumed that damaged DNA either is or becomes a mutation. He has assumed that DNA damage that does not become a mutation is either repaired – or leads to apoptosis or cellular senescence.

Dr. de Grey has made the claim that evolution has required such strong defenses against cancer that residual mutation (and, implicitly, DNA damage) is negligible. But cancer incidence increases exponentially with age up to age 80, so it is likely that the residual increases exponentially at the same time.

As recently as the 1980s it was widely believed that normal aging is associated with extensive neuron loss. Now it is established that functional decline in the aging brain is associated with increased neural dysfunction rather than neurodegeneration. [note 5] This neural dysfunction may or may not be mostly due to cellular damage that SENS is intended to fix – including causes of declining NHEJ activity. How much neuron dysfunction associated with aging is due to accumulating mutations or unrepairable nuclear DNA damage is unknown. SENS assumes without proof that nuclear DNA damage and mutation is negligible as a cause of aging (apart from cancer, apoptosis, and cellular senescence). This may be right or it may be wrong. I believe that without definitive proof, nothing should be assumed, and active investigation to determine the facts should not be neglected.

I believe the situation is not hopeless if nuclear DNA damage proves to be a significant cause of brain aging. Future molecular technologies for detection and repair of nuclear DNA damage could be significantly better than natural DNA repair enzymes. And, to simplify the required effort, the DNA repair technologies could be restricted to genes that are actively transcribed in neurons, rather than needing to repair the whole genome.

Notes

1: Best BP. Nuclear DNA damage as a direct cause of aging. Rejuvenation Res. 2009 Jun;12(3):199-208.

2: Mao Z, Bozzella M, Seluanov A, Gorbunova V. Comparison of nonhomologous end joining and homologous recombination in human cells. DNA Repair (Amst). 2008 Oct 1;7(10):1765-71.

3: Mandaville BS, Rao KS. Neurons in the cerebral cortex are most susceptible to DNA-damage in aging rat brain. Biochem Mol Biol Int 1996 Oct; 40(3):507-14.

4: Vyjayanti VN, Rao KS. DNA double strand break repair in brain: reduced NHEJ activity in aging rat neurons. Neurosci Lett. 2006 Jan 23;393(1):18-22.

5: Morrison JH, Hof PR. Life and death of neurons in the aging brain. Science. 1997 Oct 17;278(5337):412-9.