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DNA Damage and Repair and its Impact on Healthy Ageing

Periodic Reporting for period 4 - Dam2Age (DNA Damage and Repair and its Impact on Healthy Ageing)

Reporting period: 2022-03-01 to 2023-08-31

The original outdated text is replaced by the summary of the entire period given below
Our DNA-repair-deficient mouse mutants in DamAge revealed a causal link between accumulating DNA damage and aging. Although then very controversial, DNA damage is now accepted as one of the primary causes of aging, along with others, as aging is considered multi-factorial. In Dam2Age we have unequivocally identified DNA damage as the primary cause of systemic aging (Schumacher, Nature 2022) and disclosed how accumulating DNA damage affects numerous processes, and tissues resulting in systemic functional decline and multi-morbidity. In a landmark paper (Gyenis, Nat Gen. 2023), we demonstrated that accumulation of stochastic DNA lesions physically block elongating RNA polymerase II. This lowers gene expression in a gene-length-dependent manner, as the risk of DNA damage is proportional to gene size. The resulting “transcription stress” (TS) reduces and skews gene expression, preferentially of long genes and is preserved from worms to man, indicating its universal occurrence and importance (Gyenis, Nat. Gen. 2023, now confirmed by 3 other groups). Moreover, genome-wide, imbalanced gene expression explains >50% of all aging-related expression changes in post-mitotic tissues which are unable to counteract built-up of DNA lesions by dilution and repair through DNA replication. This explains why DNA repair syndromes with defective transcription-coupled repair (TCR), such as Cockayne syndrome (CS) and trichothiodystrophy (TTD), suffer from premature aging in post-mitotic tissues (brain, liver, kidney, etc.). Since transcription is the start of every cellular process, genome-wide TS affects numerous cellular systems eventually causing functional decline, cell death and thereby aging, and explains (virtually) all aging hallmarks. Hence, our findings solve one of the main unresolved, fiercely debated very long-standing enigmas in biology: the molecular basis of aging.

Previously we also discovered that premature aging, due to DNA repair deficiency, triggers a ‘survival response’, which attenuates growth and boosts resilience mechanisms by suppressing the insulin-like growth factor 1 (IGF1) somatotrophic axis in an apparent attempt to delay the accelerated aging. Indeed, we found strong similarities with the response elicited by dietary restriction (DR), the only universal intervention delaying aging. In Dam2Age we discovered why IGF1 goes also down with aging, unexplained since >4 decades. The IGF1 gene is remarkably long: 60-fold larger than the related insulin gene! Hence, it experiences age-related TS, because it captures DNA damage, lowering its expression (Gyenis, Nat. Gen. 2023). We found strong indications that the IGF1 gene is purposely long to act as a DNA damage ‘dosimeter’, which activates the ‘survival response' during episodes with high DNA, to enable survival. This reveals, that gene length is evolutionarily relevant and identifies IGF1 as an important modulator of DNA damage-driven aging (mns. in prep.).
Previously we also found that actually applying 30% DR to progeroid repair-deficient mouse mutants (which exhibit a severe growth deficit) enormously delays all aspects of premature aging and extends lifespan by 200% (!), i.e. 6-fold that in wt mice (Vermeij, Nature 2016). Of all organs the neuronal system benefitted most and even significantly improved. In Dam2Age we discovered how DR exerts such a spectacular benefit: examining TS, we found that DR reduces genome-wide TS, by lowering overall DNA damage and thereby improving gene expression and cell function. Since DNA repair mutants are hypersensitive to DNA damage, they also overrespond when DNA damage is less. This explains at least in part how DR delays aging, elusive since its discovery in 1935.

Obviously, we wished to translate the remarkable benefits of DR to patients. Since TCR-deficient CS and TTD children have severe neurodevelopmental deficits including dwarfism (due to TS in the IGF1-somatotrophic axis, see above), standard treatment includes extra nutrition to stimulate growth. Therefore, our arguments to the contrary were counterintuitive, and met with considerable resistance. Eventually, after multiple times explaining the concept and showing the evidence, parents of one child, together with their clinician and dietician, chose to carefully reduce caloric intake of their TTD patient (age 7), with severe, progressive neurological decline and poor prognosis. The effects even surpassed the already spectacular mouse findings. Her neurological decline not only stopped, but even reverted: her very severe tremors disappeared, motor performance and cognition dramatically improved, she started for the first time to walk (before she could barely crawl), talk, count, is learning reading, writing, bicycling, withstood Covid and enjoys now over 5,5 years stable health and very good QoL. Without doubt this also extended her lifespan. Importantly, she regained appetite but still receives extra nutrition, so is not starving. On this basis global nutritional guidelines for CS and TTD have been reversed and all consulted parents by CS/TTD family organization Amy and Friends (UK) report benefit. Clearly, simply reducing food works better than any medication would be expected to achieve and is the first effective treatment for any DNA repair disorder resulting from basic research, changing the prospects of CS and TTD (and perhaps other genome instability disorders). Moreover, it is easy implementable, does not require complex infrastructure, is safe, at no costs and affordable for all patients even in less wealthy countries (mns in prep). As additional spin-offs we have established a multi-disciplinary expertise center at the Erasmus MC for genome instability disorders and initiated an international clinical trial to better define the optimal nutritional needs of CS and TTD children and investigate whether other genome instability conditions such as ataxia telangiectasia and Fanconi’s anemia may also benefit.

This paradigm example establishes translation to humans and the systemic preservative anti-ageing potential of nutritional interventions to install a resilient state by temporarily suppressing growth and boosting stress resistance (e.g. anti-oxidant and immune defenses). We have strong evidence that this inducible ‘survival response’, can be triggered by short-term fasting and exploited as nutritional preconditioning to strongly reduce ischemia reperfusion injury associated with surgery and organ transplantation (with clinical trials ongoing) and for preventing the short- and long-term side effects of genotoxic chemo- and radiotherapy in cancer treatment (preclinical studies, supporting clinical trials). Moreover, caloric reduction is also predicted to delay progression of early stages of dementias such as Alzheimer and Parkinson diseases, etc. Hence, nutrition has enormous medical applications. Clearly, the basic findings in Dam2Age have wide-ranging applications in major medical areas, with enormous potential, far exceeding the rare DNA repair syndromes, with which we started.
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