Table 1. Preclinical and clinical studies on DR in aging and neurodegenerative diseases.

Model	Reference	Type of DR	DR effects on inflammatory or other brain pathology markers	DR effects on cognitive or motor functions	DR effects on imaging measures
Aging
Rodents	Morgan et al., 1999; Lee et al., 2000	30–40% DR	↓ Age-related increased of activation markers on microglia (e.g., MHCII) or astrocytes (e.g., GFAP); ↓ inflammatory genes
	Kaur et al., 2008	IF	↓ Age-related changes in brain expression of NCAM, PSA-NCAM, and GFAP
	Singh et al., 2012	IF	↓ Protein oxidative damage; ↑ markers of synaptic plasticity in the hippocampus	Ameliorates motor coordination, cognitive skills
Nonhuman primates	Qin et al., 2006	30% DR	↓ Aβ deposition
	Willette et al., 2010	30% DR	Attenuates the relation between IL-6 and brain volume loss		Attenuates the relation between IL-6 and brain volume loss
	Willette et al., 2012	30% DR	Attenuates the negative correlation between homocysteine and global gray matter volume		Attenuates the negative correlation between homocysteine and global gray matter volume
	Colman et al., 2009; Kastman et al., 2012; Sridharan et al., 2012; Sridharan et al., 2013	30% DR (University of Wisconsin study)	↓ Age-related astrogliosis (↓ GFAP in hippocampus and entorhinal cortex)	Preserves motor performance	No effect on corpus callosum integrity; ↑ FA in several white matter regions; ↓ GM volume loss; ↓ brain iron accumulation
Humans	Leclerc et al., 2020; Witte et al., 2009	25–30% DR		Ameliorates memory performance	↓ C reactive protein and insulin levels
	Blumenthal et al., 2010; Smith et al., 2010	DASH diet (Appel et al., 1997) and DR		Improves cognitive function
AD
Rodents	Patel et al., 2005; Wang et al., 2005; Wu et al., 2008; Schafer et al., 2015	30–40% DR	↓ Aβ and phospho-tau deposition; ↓ astrocyte activation	Improved performance in cognitive tests
	Halagappa et al., 2007; Brownlow et al., 2014	Different DR regimens based on individual calorie consumption; 35–40% DR	No effects	Improved age-related behavioral impairments; rescued associative memory deficits
Humans	Horie et al., 2016	DASH diet + DR 500 kcal/d or 25% DR		Improvement in cognitive functions
PD
Rodents	Duan and Mattson, 1999	IF	↓ Damage to SN neurons	↓ Motor deficits
	Maswood et al., 2004	30% DR	↑ Levels of dopamine and dopamine metabolites in the striatal region	↑ Locomotor activity	No differences in presynaptic dopaminergic activity in vivo
	Armentero et al., 2008	IF	No effect on nigrostriatal degeneration
	Griffioen et al., 2013	IF	NA	Ameliorates autonomic function	NA
Nonhuman primates	Maswood et al., 2004	30% DR	↑ Levels of dopamine and dopamine metabolites in the striatal region	↑ Locomotor activity	No differences in presynaptic dopaminergic activity in vivo
ALS
Rodents	Pedersen and Mattson, 1999	IF		Accelerates disease onset and shortens disease duration
	Hamadeh et al., 2005	40% DR		Accelerates disease onset
MS
Rodents	Esquifino et al., 2007	66%	Alters lymphocytes composition in lymphoid organs, ↓ IFN-γ production	Prevents EAE
	Piccio et al., 2008	40% DR	↑ Corticosterone and adiponectin; ↓ leptin and IL-6	Ameliorates EAE clinical course
	Kafami et al., 2010	IF		Ameliorates EAE clinical course and reduces incidence of disease
	Cignarella et al., 2018	IF	↓ Th17 cells, ↑ T regulatory cells in small intestine lamina propria, altered gut microbiota	Ameliorates EAE clinical course and reduces incidence of disease
	Jordan et al., 2019	IF	↓ Monocyte infiltration in the spinal cord, ↓ TNFα, IL-1β, CXCL2, and CXCL10	Ameliorates EAE clinical course and reduces incidence of disease
Humans	Saadatnia et al., 2009	Ramadan fasting		Well tolerated, no differences in relapse rate
	Etemadifar et al., 2016	Ramadan fasting		Improves physical health and mental health composites of QOL
	Choi et al., 2016	FMD + Mediterranean or ketogenic diet		Improves QOL
	Fitzgerald et al., 2018	22% DR or IF		Improves mood
	Cignarella et al., 2018	IF	↓ Leptin

Summary of the main studies on the effects of DR on aging and neurodegenerative and neuroinflammatory diseases. FA, fractional anisotropy. GM, gray matter; NA, not applicable; NCAM, neural cell adhesion molecule; PSA, polysialylated; QOL, quality of life; SN, substantia nigra.