Reduced tumor growth and DNA damage from radiation in time-restricted fed rodents | Satchin Panda
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Rapidly dividing cells, such as those in skin and hair, are highly vulnerable to the DNA-damaging and cancer-causing effects of radiation. Hair follicles, however, have potent circadian-regulated repair mechanisms that correct and repair damaged DNA, allowing an irradiated hair cell to regenerate, unharmed. Experiments in mice have shown that these mechanisms are particularly effective after fasting. These findings have powerful implications for humans in terms of the timing of cancer surgeries and treatments so as to capitalize on the body's circadian-regulated protective mechanisms. In this clip, Dr. Satchin Panda describes how circadian rhythms influence DNA damage and repair, especially in the setting of time-restricted eating.
- Rhonda: Have you guys ever looked at, like, DNA damage or repairing any sort of challenge? Like if you irradiate... Like animals that are eaten, you know, on a time-restricted, you know, feeding sort of schedule where they're eating their food, being fed their food, you know, within 10 hours or so, and then challenge them.
- Satchin: With radiation or something?
- Rhonda: Can they, like, repair the damage better because they're fasting longer?
- Satchin: Yeah. So the circadian clock itself has a huge impact on DNA damage repair and radiation damage repair. So a few years ago we had done a simple experiment that got highlighted in National Cancer Institute website. There's a very simple, straightforward experiment. We always asked...we asked a very simple question, that is, "How come humans' skin is always exposed to sunlight or UV radiation and many people get skin cancer but they never get hair cancer?" Because a hair follicle has the most rapidly dividing cells. And so one would expect that they must be most sensitive to radiation damage. And if there is any radiation damage, that's where the tumors will start. And we rarely see that. So we went back and checked and we realized that the hair follicles at the base of the hair actually have a very strong circadian rhythm. And every evening that circadian clock repairs all the damaged DNA and makes sure that the hair can grow back the next day, next morning. And then we asked, "So what is the real significance in real life?" So we took these mice and then did a simple experiment. That is, you know, for many bone marrow transplant experiments, mice are irradiated, and then their bone marrow is depleted and one can put the new bone marrow in. And they get irradiated to the same extent as humans do. They don't die, they actually survive pretty well. And if we irradiate mice in the morning, 8:00, then those mice lose 85% of their hair. And if we irradiate the same mice with the same dose at 8:00 in the evening they retain 85% of their hair. So it's a big, like really, black and white difference because these morning irradiated mice essentially become bald very quickly. And the evening irradiated mice, they keep their hair perfectly fine. Now if we take circadian clock mutant mice where the circadian clock is absent, irrespective of what time we irradiate the mice, they always lost hair. Of course the story was much more about what...which DNA repair enzymes are regulated by clock and how this clock works, but this is a very simple, straightforward experiment. And similarly people have also shown many patients do go through partial hepatectomy. Or people who have liver cancer, part of the liver is resected, and then the liver grows back. And, in mouse experiments at least, if partial hepatectomy is done in the evening, then those mice recover much faster than those where the hepatectomy was done in the daytime. So that has inspired some people to think about this surgery time, what time surgery should be done and irradiation should be done. So these are some just new ideas that have just come up in animal models in the last five to 10 years, so it will take some time to really get some traction in human studies.
- Rhonda: Yeah. It will be interesting to figure out whether it's, you know, the combination of is it because they're, you know, getting more rest during that time, during the evening, and then they're resting, fasted and resting, and so, you know, the combination of them all.
- Satchin: Yeah. So we know that the tumors grow slower in mice that eat only within certain times. So time-restricted fed mice, if we just implant a tumor, then the tumor will not grow as much as in the mice that eat randomly the same number of calories.
- Rhonda: Wow.
- Satchin: And that also jives with another piece of data that came from Ruth Patterson's group that women who fast for 13 hours overnight are protected from breast cancer.
- Rhonda: They have, like, a 36% lower breast cancer occurrence.
- Satchin: Yeah, yeah.
- Rhonda: Yeah. So that's really cool. I wonder if with at least the animal experiments where you're implanting the tumor and they're fed at a time-restricted feeding schedule, then if they're having more apoptosis, more autophagy, more DNA repair, all these things are all sort of simultaneously happening because they're in a fasted state for longer?
- Satchin: Yeah.
- Rhonda: Possibly?
- Satchin: So it's possible.
- Rhonda: Yeah.
- Satchin: Yeah.
- Rhonda: Very cool and interesting.
Programmed cell death. Apoptosis is a type of cellular self-destruct mechanism that rids the body of damaged or aged cells. Unlike necrosis, a process in which cells that die as a result of acute injury swell and burst, spilling their contents over their neighbors and causing a potentially damaging inflammatory response, a cell that undergoes apoptosis dies in a neat and orderly fashion – shrinking and condensing, without damaging its neighbors. The process of apoptosis is often blocked or impaired in cancer cells. (May be pronounced “AY-pop-TOE-sis” OR “AP-oh-TOE-sis”.)
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
The body’s 24-hour cycles of biological, hormonal, and behavioral patterns. Circadian rhythms modulate a wide array of physiological processes, including the body’s production of hormones that regulate sleep, hunger, metabolism, and others, ultimately influencing body weight, performance, and susceptibility to disease. As much as 80 percent of gene expression in mammals is under circadian control, including genes in the brain, liver, and muscle.[1] Consequently, circadian rhythmicity may have profound implications for human healthspan.
- ^ Dkhissi-Benyahya, Ouria; Chang, Max; Mure, Ludovic S; Benegiamo, Giorgia; Panda, Satchidananda; Le, Hiep D., et al. (2018). Diurnal Transcriptome Atlas Of A Primate Across Major Neural And Peripheral Tissues Science 359, 6381.
A major contributing factor to aging, cellular senescence, and the development of cancer. Byproducts of both mitochondrial energy production and immune activity are major sources of DNA damage. Additionally, environmental stressors can increase this base level of damage. DNA damage can be mitigated by cellular repair processes; however, the effectiveness of these processes may be influenced by the availability of dietary minerals, such as magnesium, and other dietary components, which are needed for proper function of repair enzymes.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
Restricting the timing of food intake to certain hours of the day (typically within an 8- to 12-hour time window that begins with the first food or non-water drink) without an overt attempt to reduce caloric intake. TRE is a type of intermittent fasting. It may trigger some beneficial health effects, such as reduced fat mass, increased lean muscle mass, reduced inflammation, improved heart function with age, increased mitochondrial volume, ketone body production, improved repair processes, and aerobic endurance improvements. Some of these effects still need to be replicated in human trials.
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