Nutritional Preconditioning in Cancer Treatment in Relation to DNA Damage and Aging

Abstract

Dietary restriction (DR) is the most successful nutritional intervention for extending life span and preserving health in numerous species. Reducing food intake triggers a protective response that shifts energy resources from growth to maintenance and resilience mechanisms. This so-called survival response has been shown to particularly increase life and health span and decrease DNA damage in DNA repair–deficient mice exhibiting accelerated aging. Accumulation of DNA damage is the main cause of aging, but also of cancer. Moreover, radiotherapies and most chemotherapies are based on damaging DNA, consistent with their ability to induce toxicity and accelerate aging. Since fasting and DR decrease DNA damage and its effects, nutritional preconditioning holds promise for improving (cancer) therapy and preventing short- and long-term side effects of anticancer treatments. This review provides an overview of the link between aging and cancer, highlights important preclinical studies applying such nutritional preconditioning, and summarizes the first clinical trials implementing nutritional preconditioning in cancer treatment. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Chemotherapy Side-Effects: Not All DNA Damage Is Equal

“…If, however, the number of DNA lesions becomes too high for the repair machineries to tackle, patients treated with various DNA damaging treatments such as radio-and chemotherapy would be left with elevated levels of persisting DNA lesions. The chemotherapy side-effects observations made in Table 1 strengthen the hypothesis that elevated exposure would lead to accelerated aging later in life [12,15,156] and is in line with the DNA damage theory of aging [155,163]. Likewise, children with inborn mutations in DNA repair processes or nuclear integrity show segmental progeroid aging, affecting only a subset of tissues and organs [157,[164][165][166].…”

“…Lastly, identification of toxicity-related biomarkers could aid in better monitoring and early detection of overtreatment and side-effects, while these are potentially still reversible. Better insight into development of side-effects facilitates the implementation of nutritional or chemical interventions to reduce toxicity [9,156,[167][168][169]. Patients can benefit from the aforementioned strategies, resulting in increased wellbeing, in both the short and long term.…”

“…However, most lesions likely arise from endogenous sources, such as reactive by-products of normal metabolism [151,153,154]. Together, this results in a broad variety of chemical modifications to our DNA, ranging from spontaneous deamination and hydrolysis or subtle base modifications to bulky helix distorting lesions, inter-and intrastrand DNA crosslinks, or single-and double-stranded DNA breaks [155,156]. Indirectly, also R-loop formation (hybridization of mature mRNA with double-stranded DNA), as a consequence of transcription stalling, can be considered as DNA damage.…”

Psychosexual development, sexual functioning and sexual satisfaction in long‐term childhood cancer survivors: DCCSS‐LATER 2 sexuality substudy

“…In previous studies, 5,16–18,20 where significant differences were reported, CCS and references up to age 51 were included in the comparison. Cancer treatments might accelerate aging and put survivors at an increased risk of developing various health conditions earlier than the general population 39 . Therefore, differences between CCS and the general population with regard to problems with sexual functioning and sexual satisfaction may arise at a higher age than we were able to study.…”

Gene expression changes in cerebellum induced by dietary restriction

“…DR increases health- and lifespan in organisms ranging from yeast to primates with benefits throughout the body ( Lee et al, 2021 ; Green et al, 2022 ). In rodents and primates, DR has been shown to reduce age-related decline in motor and cognitive function and age-related nervous system pathologies, and to increase resistance to oxidative, metabolic, and excitotoxic insults ( Valdez et al, 2010 ; Wahl et al, 2016 ; Mattison et al, 2017 ; van den Boogaard et al, 2021 ). Furthermore, DR has been shown to reduce neurological deficits and nervous system pathologies in a subset of mouse models for age-related neurodegenerative diseases ( Xie et al, 2020 ; Green et al, 2022 ; Mitchell and Mitchell, 2022 ).…”