In previous studies we had shown that intermittent fasting (IF) is neuroprotective in rodent models of Alzheimers and Parkinsons diseases and stroke. The neuroprotective mechanism involves induction of a mild beneficial cellular response as indicated by increased expression of heat-shock proteins and brain-derived neurotrophic factor (BDNF). We have found that IF increases BDNF levels in the brain, ameliorates diabetes, suppresses neuronal degeneration in the striatum and cortex, and extends survival in a mouse model of Huntingtons disease. In a more recent study we have shown that dietary restriction is beneficial in a monkey model of Parkinsons disease. We have recently provided evidence that dietary lipids may modulate risk of AD and ALS. Levels of cholesterol and long-chain ceramides are increased in membranes of cells in the brains of AD patients and spinal cords of ALS patients. Additional data in studies of cell culture and animal models of AD and ALS suggest that ceramides may play an important role in the cell death process in these disorders. Because levels of cholesterol, sphingolipids and ceramides can be modulated by changes in diet, our data suggest that dietary lipids may modify the vulnerability of neurons to age-related diseases. In other studies we have shown that IF can improve glucose metabolism (increased insulin sensitivity) and cardiovascular risk factors (decreased blood pressure and superior cardiovascular stress adaptation) in rats. The latter effects of IF were mimicked by intermittent feeding of rats a diet supplemented with 2-deoxyglucoe, a non-metabolizable analog of glucose. Interestingly, IF and caloric restriction also increase heart rate variability in a manner suggesting that these diets increase parasympathetic tone, while decreasing sympathetic tone. Thus, IF and caloric restriction exert physiological actions that would be expected to reduce the risk of diabetes and cardiovascular disease. In our efforts to establish the mechanism by which dietary restriction protects neurons we have found that dietary restriction increases the expression of mitochondrial uncoupling proteins and enzymes of the plasma membrane redox system, resulting in a decrease in oxidative stress and stabilization of cellular energy homeostasis in neurons. We have performed massive gene array analysis of the effects of gene expression in multiple brain regions as part of the AGEMAP (atlas of gene expression in mouse aging project) project. In another study we correlated changes in brain gene expression with behavioral, endocrine and biochemical alterations male and female rats maintained on diets with different levels of energy. In human studies we have found that an alternate day caloric restriction diet improves symptoms and decreases markers of oxidative stress and inflammation in asthma patients. In a meal frequency study, we found that consuming one large meal versus three smaller meals each day results in complex changes in physiology, some of which may be beneficial and others detrimental for health. Most recently, we have screened a panel of 'biopesticides'to identify naturally occurring chemicals that can activate adaptive stress response pathways in neurons and so can protect the neurons against dysfunction and degeneration in experimental models of neurodegenerative disorders. This project identified the phytochemical plumbagin as a lead candidate neuroprotective agent that we are currently further evaluating in preclinical studies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Aging
Zip Code
Hou, Yujun; Lautrup, Sofie; Cordonnier, Stephanie et al. (2018) NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115:E1876-E1885
Mattson, Mark P; Arumugam, Thiruma V (2018) Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab 27:1176-1199
Mattson, Mark P; Moehl, Keelin; Ghena, Nathaniel et al. (2018) Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci 19:63-80
Raefsky, Sophia M; Furman, Ran; Milne, Ginger et al. (2018) Deuterated polyunsaturated fatty acids reduce brain lipid peroxidation and hippocampal amyloid ?-peptide levels, without discernable behavioral effects in an APP/PS1 mutant transgenic mouse model of Alzheimer's disease. Neurobiol Aging 66:165-176
Nigam, Saket M; Xu, Shaohua; Kritikou, Joanna S et al. (2017) Exercise and BDNF reduce A? production by enhancing ?-secretase processing of APP. J Neurochem 142:286-296
Raefsky, Sophia M; Mattson, Mark P (2017) Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance. Free Radic Biol Med 102:203-216
McGee-Lawrence, Meghan E; Wenger, Karl H; Misra, Sudipta et al. (2017) Whole-Body Vibration Mimics the Metabolic Effects of Exercise in Male Leptin Receptor-Deficient Mice. Endocrinology 158:1160-1171
Liu, Yong; Zhou, Li-Jun; Wang, Jun et al. (2017) TNF-? Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury. J Neurosci 37:871-881
Yao, Pamela J; Manor, Uri; Petralia, Ronald S et al. (2017) Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons. Mol Biol Cell 28:387-395
Mattson, Mark P; Longo, Valter D; Harvie, Michelle (2017) Impact of intermittent fasting on health and disease processes. Ageing Res Rev 39:46-58

Showing the most recent 10 out of 80 publications