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DNA Damage and Repair and its Impact on Healthy Ageing

Periodic Reporting for period 3 - Dam2Age (DNA Damage and Repair and its Impact on Healthy Ageing)

Reporting period: 2020-09-01 to 2022-02-28

The Dam2Age project is based on a preceding ERC advanced grant DamAge, which pioneered an initially highly controversial connection we discovered between time-dependent accumulating damage to our DNA and many -if not all- features of aging. In DamAge we reached the stage that the process of aging could be accelerated and targeted to specific organs by manipulating specific DNA repair systems. For this research we generated a series of DNA repair-deficient mice that closely model rare human DNA repair disorders, including Cockayne Syndrome (CS) and Trichothiodystrophy (TTD), in which children display many severe features of accelerated aging, most dramatically neurodegeneration, often limiting life expectancy to childhood. We found that the severity of the repair defect determines the rate of segmental aging; the repair pathway affected influences which organs age fast; conditional repair mutant mice allowed us to target accelerated aging to any organ. Ingeniously, accelerated aging and persistent DNA damage both appeared to trigger a ‘survival response’ that attenuates growth and boosts defense and maintenance systems, likely an effort to slow down aging. Indeed, it closely resembled the response to dietary restriction (DR, i.e. reduced intake of healthy nutrition), the only universal intervention known to delay aging. Interestingly, we found that actual DR applied to tiny progeroid repair mutants dramatically extends their life- and healthspan. E.g. lifespan of Ercc1Δ/- repair mice, mimicking XFE syndrome in man, trippled upon 30% DR (Vermeij et al., Nature 2016). The dementia-like neurodegeneration in these mice is even retarded up to 30-fold(!) disclosing extremely powerful untapped reserves, unleashed by nutritional interventions. Also we discovered that gene expression in post-mitotic organs declines in accelerated and normal aging due to accumulating stochastic transcription-blocking DNA lesions and that DR counteracts this genomic erosion. In Dam2Age we focus on the cross-talk between DNA damage, aging and nutritional interventions with emphasis on the relevance for normal aging and elucidate the underlying molecular mechanisms. We intend to use our unique -for DR research superior- mouse models to search for effective nutritional-pharmacological DR mimetics. This serves as a stepping stone towards a potent universal therapy for a range of repair-deficient progeroid syndromes and prevention of natural aging-related diseases, most urgently dementia’s such as Alzheimer’s and Parkinson diseases, and extend healthspan, addressing the most important global health care and socio-economic needs.
An important mechanistic aspect of the DNA damage - aging connection is our finding that accumulating DNA lesions interfere with gene expression by blocking transcription, causing transcription stress, which reduces transcriptional output. This is particularly problematic for non-proliferative tissues, which are unable to counteract built-up of DNA lesions by dilution through DNA replication. This explains why in DNA repair syndromes with genetic defects in transcription-coupled repair (TCR), such as CS and TTD, the post-mitotic tissues, including the neuronal system, liver, kidney and skeleton, are specifically suffering from premature aging. Since DNA lesions are stochastic, transcription stress affects expression in a gene length-dependent fashion, leading to reduced and dysbalanced transcriptional output, which predictably eventually instigates functional decline, cell death and thereby aging. We also discovered that the ‘survival response’ triggered by DR involves metabolic redesign, and e.g. boosting anti-oxidant defenses, thus lowering endogenous DNA damage load and in turn transcription stress and aging, revealing at least one way by which DR slows aging.
Obviously, it is important to see whether the remarkable beneficial effects exerted by DR in our progeroid mouse mutants also apply to corresponding patients. Since TCR-deficient CS and TTD patients have severe neurodevelopmental deficits including dwarphism, current treatment policy includes extra nutrition often by PEG, because patients have minimal apatite. Therefore, our arguments that these children should actually get less instead of more food was counterintuitive, and met with considerable resistance. Nevertheless, eventually, when parents, in close consultancy with their clinician and dietician, chose to partially reduce caloric intake of their child (at the age of 7), suffering from TTD and severely progressive neurological decline, the effects even surpassed the the already dramatic mouse findings. Her neurological decline not only stopped, but motor performance and cognition even dramatically improved, her very severe tremors disappeared, she started for the first time walking (whereas before she could barely crawl), talking, counting, writing and enjoys now well over 2 years very stable health, without any significant illness. The strong connection with reducing food intake and promoting health became even more apparent when the dietician, concerned about some weight loss, urged the parents to temporarily increase caloric intake resulting in immediate re-appearance of tremors, which disappeared again when caloric intake was reduced. This occurred twice, indicating a direct relationship between nutritional intake and neuro(dys)function. This overwhelming improvement, which is not anecdotal, but exemplary and consistent with many other observations, has already at a recent international conference led to a complete reversal of the guidelines for the nutritional care of TTD and Cockayne syndrome (CS) children: instead of more, CS/TTD patients are advised to receive less food (manuscript in preparation). This example establishes the translation from mouse to humans and the wide-spread preservative anti-ageing potential of nutrition, when used as medicine, which we predict will also have important potential for other age-related diseases including dementias, such as Alzheimer and Parkinson diseases, fronto-temporal dementia, but also ischemia reperfusion injury associated with any surgery and organ transplantation, and for preventing the short- and long-term side effects of genotoxic chemo- and radiotherapy in cancer treatment.
The above described clinical breakthrough and the insight into the underlying molecular mechanisms has prompted us to initiate four clinical trials and establishing an officially recognized (inter)national expertise center at the Erasmus Medical Center for the treatment of genome instability disorders. In the same context we are in the process of acquiring financial support for a clinical trial of CS and TTD patients to more precisely monitor the effect of nutritional interventions on a series of health parameters of affected children and optimize and tailor food composition and quantity. We are also investigating the effect of nutritional preconditioning on genotoxic chemo- and radiotherapy in cancer treatment and intend in the future to initiate clinical trials in this area. Clearly, the basic findings made in DamAge and now Dam2Age have wide-ranging applications in major medical areas, with enormous potential, far exceeding the initial, rare DNA repair syndromes.
This slide shows the advertisement of the first Nature Conference on Ageing, Health and Rejuvenation