Periodic Reporting for period 2 - Dam2Age (DNA Damage and Repair and its Impact on Healthy Ageing)
Reporting period: 2019-03-01 to 2020-08-31
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.