Dietary restriction in senolysis and prevention and treatment of disease

Figures & data

Table 1. Diet and impact on lifespan and disease in selected preclinical studies.

Organism	Diet	Results	Molecular markers	Reference
Mouse (OF1, female)	ADF	↓ lymphoma incidence	↓ mitochondrial ROS ↑ splenic superoxide dismutase activity	(Descamps et al. 2005)
Mouse (C57BL/6J, male)	ADF	modulation of adipocyte function ↔ body and adipose tissue weight	↔ Adiponectin	(Varady et al. 2007)
Mouse (C57BL/6, DBA/J2, male & female)	Comparison of DR regimes	fasting is required for CR-induced metabolic benefits and lifespan extension	↑ insulin sensitivity ↑ fatty acid oxidation ↑ glucose sensitivity	(Pak et al. 2021)
Rhesus monkey (male & female)	CR	↓ aging-related deaths ↓ onset of age-associated pathologies: diabetes, cancer, cardiovascular disease & brain atrophy	↓ epigenetic age-associated drift	(Colman et al. 2009; Maegawa et al. 2017)
Rhesus monkey (male & female)	CR	↓ cancer incidence		(Mattison et al. 2017)
Mouse (C57BL/6J background)	CR	↓ aging-induced changes in lung ↑ epithelial cell survival in injured lung	↑ mitochondria & respiration ↓ inflammation	(Hegab et al. 2019)
Mouse (C56BL/6J, male)	CR with/without circadian alignment	↑ 30% or 35% increase in lifespan (without or with circadian alignment)	↓ age-related genes in liver	(Acosta-Rodríguez et al. 2022)
Mouse/rat – breast cancer model (MMTV-TGF-Α/C57BL/6/Sprague-Dawley, female)	CR	↓ expression of proteins involved in the mTOR & IGF-I signaling pathways in mammary tissues	↑ pAMPK ↓ IGF-I ↓ mTOR	(Dogan et al. 2011), (Jiang, Zhu, and Thompson 2008; Dogan et al. 2011)
Rat (Sprague-Dawley, male)	CR	preservation of muscle mass in middle-aged rats but not younger rats	↓ mTOR	(Chen et al. 2019)
Mouse (TG2576, female)	CR	prevention of amyloid neuropathology	↑ Sirt1 expression ↑ NAD^+	(Qin et al. 2006)
Mouse/rat – hypertension model (Wild type/Prkaa2^tm1.1Vio mutant; Sprague-Dawley; both male)	CR	↑ left ventricular function	↓ serum brain natriuretic protein ↑ mitochondrial biogenesis	(Niemann et al. 2022)
Mouse (C57BL6, male)	CR		↓ age-associated DNA methylation drift in hippocampus	(Hadad et al. 2018)
Mouse – breast cancer model (MMTV-TGF-Α/C57BL/6, female)	CR (chronic or intermittent)	↓ tumor growth ↑ adiponectin in mammary fat pads in tumor-free mice in intermittent CR ↓ adiponectin signal in mammary fat pad in tumor-bearing mice	↓ leptin, ↔ adiponectin ↑ adiponectin/leptin ratio	(Rogozina et al. 2011)
Mouse – breast cancer model (BALB/CJ + 4T1, female)	CR/FMD	↓ primary breast cancer growth and metastasis	↓ CD11b^+Gr1^+ immune cells (tumor-promoting) ↑ CD4^+ and CD8^+ T cells (tumor-fighting)	(Pomatto-Watson et al. 2021)
Mouse – allogenic tumor graft model (C57BL/6J, male & female)	CR/KD	↓ cancer growth in CR but not KD	↓ stearoyl-CoA-desaturase ↓ lipid availability (CR)	(Lien et al. 2021)
Caenorhabditis elegans	DR (removal of food after larval stage)	↑ lifespan ↑ resistance to oxidative stress ↑ thermotolerance		(Lee et al. 2006)
Saccharomyces cerevisiae	FMD (switch nutrient-rich to water every 48 h, 3 cycles of PF during the lifespan)	↑ medium & maximum lifespan ↑ stress resistance to hydrogen peroxide		(Brandhorst et al. 2015)
Mouse (C57BL/6, female)	FMD (very low calorie/low protein for 4 days twice a month)	↓ cancer incidence, inflammation in tissues (lymph nodes, liver) ↓ immunosenescence ↑ hippocampal neurogenesis	↓ IGF-1 signaling	(Brandhorst et al. 2015)
Mouse (c57BL/6/BKS type 1 or Type 2 diabetes model, male)	FMD	↑ generation of insulin-producing β-cells	↑ Sox17, Ngn3	(Cheng et al. 2017)
Drosophila melanogaster	IF	↑ lifespan ↓ late-life gut pathology ↑ gut-barrier function		(Catterson et al. 2018)
Mouse – obese (C57BL/6J, BECN1^+/-, LAMP2^-/-, male & female)	IF	↑ beta cell survival ↑ glucose tolerance ↑ glucose-stimulated insulin secretion	↑ autophagy-lysosome pathway ↑ NEUROG3 (marker of pancreatic regeneration)	(Liu et al. 2017)
Mouse (tissue-specific ATG^-/-, male)	IF (isocaloric twice-a-day feeding)	prevention of age/obesity-associated metabolic defects ↓ adiposity ↑ muscle mass.	↑ autophagy ↓ gluconeogenesis ↑ pAMPK	(Martinez-Lopez et al. 2017)
Rat – spinal cord injury (Sprague-Dawley, male)	IF	neuroprotection after acute spinal cord injury	↑ autophagy ↑ lysosomal function ↑ pAMPK	(Yuan et al. 2021)
Rat – myocardial infarction (Wistar, male)	IF	↑ glycemic control protection of myocardium against ischemia-induced cell damage & inflammation	↓ leukocyte infiltration ↓ plasma IL-6 ↑ adiponectin	(Wan et al. 2010)
Mouse – mammary and skin tumors (various transgenic mice, female)	IF	↑ anti-tumor effects in combination with chemotherapy & targeted therapy	↑ pAMPK ↑ SIRT7	(Tang et al. 2021)
Mouse (CD-1, male)	IF	↑ long-term memory and cortical thickness ↓ oxidative stress	↓ HDL, cholesterol,	Li, Wang, and Zuo 2013
Mouse (C57BL/6, male)	KD	↓ midlife mortality ↓ obesity ↑ memory ↔ maximum lifespan	↓ insulin, ↓ mTOR, protein synthesis pathways ↑ PPARα pathway in liver	(Newman et al. 2017)
Mouse (C57BL/6J background)	KD	↓ Colorectal cancer frequency via βHB	↑ HOXP ↓ epithelial proliferation, tumor growth	(Dmitrieva-Posocco et al. 2022)
Mouse (CD1-nu, female)	KD	↓ Neuroblastoma growth ↓ angiogenesis, while ↑ blood vessel maturation	↑ pAMPK ↑ ketosis ↓ glucose ↓ essential amino acids	(Aminzadeh-Gohari et al. 2017)
Mouse - COVID-19 model (C57BL/6, male)	KD	restraint of immune-dependent exacerbation of COVID	↑ tissue protective γδ T cells ↓ NLRP3 inflammasome ↓ pathogenic monocytes in lungs	(Ryu et al. 2021)
Mouse (C56BL/6J, male)	KD	↓ aging-associated myocardial remodeling & dysfunction	↑ autophagy ↓ oxidative stress ↓ ER stress	(Yu et al. 2020)
Rat – epilepsy model (Sprague-Dawley, male)	KD	↓ neuronal injury	↑ autophagy ↓ damaged mitochondria	(Wang et al. 2018)
Mouse (C57BL/6JN, male)	KD	prevention of age-related decrease in mitochondrial content	↑ mitochondrial citrate synthase ↑ complex I ↑ complex IV	(Zhou et al. 2021)
Mouse (mutUNG1/wild type, sex not known)	KD	↑ mitochondrial biogenesis & bioenergetics	↑ mitochondrial mass ↑ PGC1α ↑ SIRT3	(Hasan-Olive et al. 2019)
Mouse (C57BL/6, male)	KD	↑ median lifespan & survival	↑ acetylation ↓ mTORC1 signaling	(Roberts et al. 2017)
Rat (Sprague-Dawley, male)	KD	↑ brain health & increase of overall health via modulation of energy metabolism by acting on NAD+-dependent enzymes & their downstream pathways	↑ SIRT1 ↓ PARP-1 ↓ 8-hydroxy-2′-deoxyguanosine ↑ hippocampal NAD^+/NADH ↓ DNA damage	(Elamin et al. 2018)
Mouse – glaucoma model (DBA/2J, male & female)	KD	anti-inflammation & neuroprotection in glaucoma	↓ TNFα ↓ IL-6 ↓ NOS2 ↓ pAMPK ↓ NLRP3 inflammasome	(Harun-Or-Rashid and Inman 2018)
Rat – Parkinson’s disease model (Wistar, male)	KD	↑ locomotor activity improvement normalization dopamine turnover in the striatum, KD may support late functional compensatory mechanisms for neurodegeneration		(Kuter et al. 2021)
Mouse – pulmonary fibrosis (male)	KD	↓ pulmonary fibrosis	↑ autophagy ↓ PI3K/AKT/mTOR signaling pathway	(Mu et al. 2021)
Mouse – Alzheimer’s model (APP C57BL x FVB, Female)	KD	↓ body weight ↔ cognitive function	↓ Aβ protein in brain	(Auwera et al. 2005)
Mouse – Alzheimer’s model (5XFAD C57Bl6, male)	KD	↑ spatial learning, working memory ↑ neurons in hippocampus and cortex	↓ Aβ protein in brain ↓ microglial activation	(Y. Xu et al. 2022)
Caenorhabditis elegans	TF	↓ mortality in exposed individuals, variable effects in F1-3 generations ↑ mortality in F4 generation		(Ivimey-Cook et al. 2021)
Mouse (C57BL/6J, male)	TF (24 h)	↑ antioxidant responses in skeletal muscle	↓ oxidative stress ↑expression of Nrf2-dependent genes	(Lettieri-Barbato et al. 2020)
Mouse (wild type C57BL6 or Fgf21^-/-, male & female)	TF (24 h)		↓ oxidative stress response	(Kawakami et al. 2022)
Mouse – hypertension model (C56BL6, male & female)	TRF	↓ systolic blood pressure ↑ kidney function	↓ IL-6, IL-1β	(Sims et al. 2022)
Mouse – chronic cerebral hypoperfusion model (C57BL6, male)	TRF	↑ learning ability ↓ neuropathology	alterations of DNA methylation	(Selvaraji et al. 2022)
Drosophila melanogaster	TRF	↑ life and healthspan with 6 h feeding, 20 h fasting starting mid-morning between days 10 and 40 ↓ or ↔ with other schedules (e.g. same feeding pattern in older flies, i.e. day 40-50; 24 h fasting followed by 1-2 days ad libitum feeding)	↑ circadian expression of autophagy mediators	(Ulgherait et al. 2021)

Various studies have shown beneficial effects of dietary restriction (DR) on health and lifespan in animal models.

Abbreviations: ADF: alternate-day fasting; CR: caloric restriction; DIF: diurnal intermittent fasting; FMD: fasting-mimicking diet; GH: growth hormone; IF: intermittent fasting; KD: ketogenic diet; TF: transient fasting; TRF: time-restricted feeding.

Signs: ↑: increase/improvement; ↓: decrease/attenuation; ↔: no effect.

Table 2. Diet and impact on lifespan and disease in selected human studies.

Population and type of trial	Diet / number of completed participants	Diet	Results	Molecular markers	Reference
Normal weight & overweight adults, RCT	CTRL = 15 ADF = 15	ADF	↓ weight ↓ fat mass cardio-protection	↑ adiponectin ↓ leptin	(Varady et al. 2013)
Healthy adults, RCT	CTRL = 19 CR = 34	CR	↑ resting energy efficiency	↓ ROS production	(Redman et al. 2018)
Adults aged 65+, observation	CR – Okinawa diet (epidemiological observation)		↑ lifespan ↓ risk for mortality from age-related diseases		(Willcox et al. 2007)
Healthy adults, RT	CTRL = 19 FMD = 19	FMD (3 months for 5 days FMD followed by 25 normal days)	↑ mesenchymal stem & progenitor cells in peripheral blood	↓ CRP ↓ IGF-1	(Brandhorst et al. 2015)
Healthy men, BCS	FMD = 8	FMD	↑ phenylalanine release in skeletal muscle	↑ net phenylalanine release ↓ circulating levels of insulin ↓ mTOR ↑ autophagy	(Vendelbo et al. 2014)
Healthy adults, RCT	CTRL = 16 FMD = 34	FMD (low sugar, calorie, protein, high in unsaturated fat)	↓ weight, trunk and total body fat mass ↓ blood pressure	↓ IGF-1	(Wei et al. 2017)
Healthy adults, BCS	IF = 14	IF	↓ weight, BMI	↑ key regulatory proteins in DNA repair ↑ proteins protective from cancer and diabetes	(Mindikoglu et al. 2020)
Men with prediabetes, RT	CTRL = 8 TRF = 8	early TRF	↑ cardiometabolic health	↑ insulin sensitivity ↑ β cell function ↓ blood pressure ↓ oxidative stress ↔ inflammation	(Sutton et al. 2018)
Overweight & obese adults	IF = 57	IF	gender & anthropometric variables impacted on the tested hormones	↓ ghrelin ↓ melatonin ↓ leptin ↔ cortisol	(Al-Rawi et al. 2020)
Women with breast cancer, NR & BCS	CTRL = 30 KD = 29	KD	↑ quality of life ↓ increase in symptom severity	↓ free T3	(Klement, Weigel, and Sweeney 2021)
Male athletes, RCT	CTRL = 10 KD = 9	KD	↓ fat mass	↓ glucose ↓ circulating insulin ↓ IL-6, TNFα	(Paoli et al. 2021)
Children with pharmacoresistant epilepsy, BCS	KD = 6	KD	↔ BMI	↓ ghrelin & des-acyl ghrelin	(Marchio, Roli, Giordano, et al. 2019; Marchio, Roli, Lucchi, et al. 2019)
Patients with glut1-deficiency syndrome & refectory epilepsy, BCS	KD = 30	KD	↔ BMI ↔ fat mass and lipid profiles	↔ ghrelin & leptin ↔ blood glucose, ↓ fasting insulin	(Amicis et al. 2019)
Overweight adults with atherogenic dyslipidemia, RCT & BCS	LFD = 20 VLCKD = 20	KD	↓ weight ↑ glycemic control & insulin sensitivity ↓ inflammation	↓ TNFα, IL-6, IL-8, MCP-1	(Forsythe et al. 2008)
Alzheimer’s disease patients, BCS	N = 10	KD	↑ Alzheimer’s Disease Assessment Scale-cognitive subscale (reverted to baseline after washout period)		(Taylor et al. 2018)
Alzheimer’s disease patients, RCT/X	N = 21	KD	↑ quality of life and daily activity scores ↓ weight, BMI	↓ HbA1c ↓ HDL, LDL, total cholesterol	(Phillips et al. 2021)
Elderly non-demented adults, BCS	N = 19	KD	↑ cognitive function (digit span test, Trail-Making Test B, and the global score)		(Ota et al. 2016)
Obese adults, BCS	VLCKD = 20	KD (very low calorie)		↑ adiponectin ↑ IL-10 ↓ insulin ↓ TNFα, CRP	(Monda et al. 2020)
Healthy adults, CC	CTRL = 12 KD = 21	KD (very low calorie)		alterations in DNA methylation	(Crujeiras et al. 2021)
Adults with epilepsy, BCS	N = 58	KD		alterations in DNA methylation (global loss)	(Pedersen et al. 2022)
Healthy adults, BCS	CTRL + regular exercise = 12 KD + regular exercise = 12	KD + regular exercise	↓ weight, fat mass	↑ adiponectin ↓ leptin	(Cipryan et al. 2021)
Adults aged 35-70 from 5 continents and 18 countries, prospective observational cohort	N = 135335	“KD-like” (observation of dietary carbohydrate and fat intake)	↑ mortality and cardiovascular disease with increasing carbohydrate intake (in particular >80% of energy intake from carbohydrates) ↓ mortality and cardiovascular disease with increasing total fat intake		(Dehghan et al. 2017)
Healthy adults, BCS	CTRL = 31 PF = 20	PF	↓ weight	↑ ketosis ↑ sirtuin expression ↑ Christensenella spp.	(Lilja et al. 2021)
Women without a known history of diabetes, BCS	TF = 121	TF (48 h)		↓ leptin ↔ adiponectin	(Gavrila et al. 2003)
Overweight adults, RCT/X	N = 11	TRF	changes in circadian gene expression, anti-aging, and autophagy markers	in the morning: ↑ ketosis, ↑ SIRT1, ↑ LC3A and ATG12 expression in blood in the evening: ↑ brain-derived neurotropic factor & mTOR expression	(Jamshed et al. 2019)
Healthy adults, RCT	CTRL = 28 Early-day TRF = 28 mid-day TRF = 26	TRF (eating for no longer than 8 h during 06:00-15:00 or 11:00-20:00)	↓ weight, fat mass ↓ HOMA-IR	↑ insulin sensitivity ↓ TNFα, IL-1β ↑ microbial diversity	(Xie et al. 2022)
Healthy adults, RCT (CALERIE study)	CTRL = 71 CR = 117 (main report)	25% CR (true CR achieved: 12% [mean])	↓ weight (bigger weight loss with food consumption earlier in the day and smaller eating windows) ↓ systolic and diastolic blood pressure ↑ thymopoiesis ↑ liver function (greater in men)	↓ LDL and cholesterol to HDL ratio, metabolic syndrome score ↓ CRP ↑ insulin sensitivity ≈ epigenetic age markers in blood samples	(Kraus et al. 2019; Spadaro et al. 2022; Fleischer et al. 2022; Dorling et al. 2021; Waziry et al. 2021; Ramaker et al. 2022)
Healthy adults, BCS	N = 5	FMD		↓ IGF-1	(Cheng et al. 2017)

Abbreviations: ADF: alternate-day fasting; BCS: baseline-controlled study; CC, case-control study (intervention versus control); CTRL: control; CR: caloric restriction; LFD: low fat diet; FMD: fasting-mimicking diet; IF: intermittent fasting; KD: ketogenic diet; NR: non-randomized; PF: periodic fasting; RCT: randomized controlled trial; RT: randomized trial; RCT/X: randomized controlled trial with crossover; VLCKD: very low carbohydrate ketogenic diet.

Signs: ↑: increase/improvement; ↓: decrease/attenuation; ↔: no effect.

Table 3. Selected studies on elimination of pathological effects caused by senescent cells, alleviating age-related diseases.

Organism	Pathology	Strategy to target senescent cells	Effect of senolysis	Reference
Mouse	Chronic kidney disease	ABT-263 (Navitoclax)	↑ renal function and repair	(Mylonas et al. 2021)
Mouse	Cigarette smoke-induced emphysema	CDKN2A knockout (p16^-/-)	↓ emphysema by promoting IGF1/Akt1 signaling	(Cottage et al. 2019)
Mouse	COVID-19 infection	Fisetin or INK-ATTAC mouse model	↓ inflammation and mortality after pathogen challenge	(Camell et al. 2021)
Mouse	Progeria	ABT-737	↑ median survival	(Ovadya et al. 2018)
Mouse	Normal aging	SSK1 (Senescence specific killing prodrug 1)	↓ inflammation, restoration of physical function	(Cai et al. 2020)
Mouse	Transplanted senescent cells	dasatinib and quercetin (D + Q)	↓ physical dysfunction, mortality hazard by 65%	(Xu et al. 2018)
Mouse	Normal aging	dasatinib and quercetin (D + Q)	↑ cardiac function and carotid vascular reactivity, lifespan	(Zhu et al. 2015)
Mouse	Chronic liver disease model	dasatinib and quercetin (D + Q)	↓ incidence of hepatocellular carcinoma ↓ senescence, senescence-associated secretory phenotype ↓ necroptosis	(Thadathil et al. 2022)
Mouse	Normal aging	Fisetin	↑ median and maximum lifespan, ↓ age-related pathology	(Yousefzadeh et al. 2018)
Mouse	Normal aging	FOXO4-p53 interfering peptide	↑ fitness, hair density and renal function	(Baar et al. 2017)
Mouse	Insulin resistance	INK-ATTAC mouse model or ABT-263 (Navitoclax)	↑ glucose metabolism and restoration of gene expression	(Aguayo-Mazzucato et al. 2019)
Mouse	Parkinson’s disease (environmental toxin model)	p16-3MR mouse model + ganciclovir	protection against toxin-induced neuropathology	(Chinta et al. 2018)
Mouse	Atherosclerosis	p16-3MR mouse model + ganciclovir	↓ streak size, ↓ expression of inflammatory markers, stabilization of fibrous caps	(Childs et al. 2016)
Mouse	Osteoarthritis	p16-3MR mouse model + ganciclovir	↓ post-traumatic osteoarthritis, ↑ cartilage development, reduced pain	(Jeon et al. 2017)
Mouse	Osteoporosis	INK-ATTAC mouse model or dasatinib and quercetin (D + Q)	↑ bone mass and strength and better bone architecture in aged mice	(Farr et al. 2017)
Mouse	Tau-dependent neurodegeneration (Alzheimer’s disease model)	INK-ATTAC mouse model	preservation of cognitive function	(Bussian et al. 2018)
Mouse (obese)	Metabolic dysfunction	INK-ATTAC mouse model	alleviation of metabolic and adipose tissue dysfunction	(Palmer et al. 2019)
Mouse (obese)	Susceptibility to ischemic injury due to obesity-induced vascular senescence	rapamycin treatment	↓ senescence by rapamycin treatment, ↔ body weight, prevention of limb necrosis and ischemic stroke	(Wang et al. 2009)
Mouse (obese)	Anxiety	INK-ATTAC mouse model or dasatinib and quercetin (D + Q)	↓ anxiety and lipid accumulation, restoration of neurogenesis	(Ogrodnik et al. 2019)
Mouse (obese)	Obesity-induced hepatocellular carcinoma (via SASP)	Hsp47 siRNA liposomes	Prevention of hepatocellular carcinoma development	(Yoshimoto et al. 2013)

Signs: ↑: increase/improvement; ↓: decrease/attenuation; ↔: no effect.

Table 4. Comparison of animal models and human studies on the effects of DR or senolysis.

Effect / finding	Animal studies and interventions	Reproduced in humans	Details	Population	Intervention	Citation
Alteration of metabolic hormones
↓ circulating IGF-1, insulin, or ↑insulin sensitivity	CR – mouse, breast cancer model (Jiang, Zhu, and Thompson 2008; Dogan et al. 2011); FMD – mouse, aged female (Brandhorst et al. 2015); mouse, diabetes model (Cheng et al. 2017); IF – mouse, obese (Liu et al. 2017); rat, myocardial infarct model (Wan et al. 2010); KD – mouse, male (Newman et al. 2017)	Yes	↓ IGF-1	Healthy adults, RT, n = 16	FMD	(Wei et al. 2017)
		Yes	↓ IGF-1	Healthy adults, BCS, n = 5	FMD	(Cheng et al. 2017)
		Yes	↓ IGF-1	Healthy adults, RT, n = 19	FMD	(Brandhorst et al. 2015)
		Yes	↓ circulating insulin	Healthy men, BCS, n = 8	FMD	(Vendelbo et al. 2014)
		Yes	↓ circulating insulin	Male athletes, RCT, n = 19	KD	(Paoli et al. 2021)
		Yes	↓ fasting insulin	Patients with glut1-def syndrome and refractory epilepsy, BCS, n = 30	KD	(Amicis et al. 2019)
		Yes	↓ circulating insulin	Obese adults, BCS, n = 20	VLCKD	(Monda et al. 2020)
		Yes	↑ insulin sensitivity	Healthy adults, RCT, n = 82	TRF (early versus late)	(Xie et al. 2022)
		Yes	↑ insulin sensitivity	Healthy adults, RCT, n = 188	CR	(Kraus et al. 2019)
Inflammation or inflammatory markers
↓ inflammation or inflammatory markers e.g. ↑ γδ T cells, ↓ NLRP3 inflammasome	CR – mouse (Hegab et al. 2019); mouse, breast cancer model (Pomatto-Watson et al. 2021); FMD – mouse, female (Brandhorst et al. 2015) ; IF – rat, myocardial infarct model (Wan et al. 2010); KD – mouse, COVID-19 model (Ryu et al. 2021); TF – mouse, male (Lettieri-Barbato et al. 2020); TRF – mouse, hypertension model (Sims et al. 2022)	Yes	↓ CRP	Healthy adults, RCT, n = 38	FMD	(Brandhorst et al. 2015)
		No	↔ inflammation	Men with prediabetes, RT, n = 16	IF	(Sutton et al. 2018)
		Yes	↓ IL-6, TNFα	Male athletets, RCT, n = 19	KD	(Paoli et al. 2021)
		Yes	↓ TNFα, IL-6, IL-8, MCP-1	Overweight adults with atherogenic dyslipidemia, RCT/BCS, n = 40	KD/VLCKD	(Forsythe et al. 2008)
		Yes	↓ TNFα, CRP; ↑ IL-10	Obese adults, BCS, n = 20	VLCKD	(Monda et al. 2020)
		Yes	↓ TNFα, IL-1β	Healthy adults, RCT, n = 82	TRF (early versus late)	(Z. Xie, Fuchs, et al. 2022)
		Yes	↓ CRP	Healthy adults, RCT, n = 188	CR	(Kraus et al. 2019)
Oxidative stress
↓ oxidative stress e.g. ↓ mitochondrial ROS production, ↑ resistance to oxidative stress	ADF – mouse, age-associated lymphoma model (Descamps et al. 2005); DR – Caenorhabditis elegans (Lee et al. 2006); TF – mouse (Li, Wang, and Zuo 2013); mouse, wild type and Fgf21-/-^# (Kawakami et al. 2022); KD – mouse (Yu et al. 2020) ^# 24 h one-off fast	Yes	↓ 8-isoprostane	Men with prediabetes, RT, n = 16	TRF (early)	(Sutton et al. 2018)
		Yes	↓ ROS production	Healthy adults, RCT, n = 53	CR	(Redman et al. 2018)
Autophagy
↑ autophagy markers	IF – mouse, obese (Liu et al. 2017); mouse (Martinez-Lopez et al. 2017); rat, spinal cord injury model (Yuan et al. 2021); KD – mouse (Yu et al. 2020); rat, epilepsy model (Wang et al. 2018); mouse, glaucoma model (Harun-Or-Rashid and Inman 2018); mouse, pulmonary fibrosis (Mu et al. 2021)	Yes	↑ LC3B-II (autophagy marker) in muscle	Healthy men, BCS, n = 8	FMD	(Vendelbo et al. 2014)
		Yes	↑ LC3A and ATG12 expression in blood	Overweight adults, RCT, n = 11	TRF	(Jamshed et al. 2019)
Epigenetic DNA methylation changes
↓ epigenetic age	CR – Rhesus monkey (Maegawa et al. 2017), mouse (Hadad et al. 2018)	?	↓ DunedinPACE of aging, ↔ other epigenetic age markers	Healthy adults, RCT, n = 197	CR	(Waziry et al. 2021)
		?	DNA methylation altered, epigenetic age not directly studied	Healthy adults, intervention versus normal controls, CC, n = 33	KD	(Crujeiras et al. 2021)
		?	DNA methylation altered (global loss), epigenetic age not directly studied	Adults with epilepsy, BCS, n = 58	KD	(Pedersen et al. 2022)
		Yes	↓ epigenetic age acceleration	Healthy adults aged 65-79, RCT, n = 120	Mediterranean diet (described by Berendsen et al. 2014)	(Gensous et al. 2020)
Clinical change
↓ weight, fat mass, BMI	IF – mouse (Martinez-Lopez et al. 2017); KD – mouse, male (Newman et al. 2017); mouse (Auwera et al. 2005)^§ § studies non-exhaustive, others have also demonstrated weight loss.	Yes	↓ weight, fat mass	Normal/overweight adults, RCT, n = 30	ADF	(Varady et al. 2013)
		Yes	↓ weight, trunk and total fat mass	Healthy adults, RT, n = 16	FMD	(Wei et al. 2017)
		Yes	↓ weight, BMI	Healthy adults, BCS, n = 14	IF	(Mindikoglu et al. 2020)
		Yes	↓ fat mass	Male athelets, RCT, n = 19	KD	(Paoli et al. 2021)
		No	↔ BMI	Children with pharmacoresistant epilepsy, BCS, n = 6	KD	(Marchio, Roli, Giordano, et al. 2019; Marchio, Roli, Lucchi, et al. 2019)
		No	↔ BMI, fat mass	Patients with glut1-def syndrome and refractory epilepsy, BCS, n = 30	KD	(Amicis et al. 2019)
		Yes	↓ weight	Overweight adults with atherogenic dyslipidemia, RCT/BCS, n = 40	KD/VLCKD	(Forsythe et al. 2008)
		Yes	↓ weight, fat mass	Healthy adults, BCS, n = 24	KD plus exercise	(Cipryan et al. 2021)
		Yes	↓ weight	Healthy adults, BCS, n = 51	PF	(Lilja et al. 2021)
		Yes	↓ weight, fat mass	Healthy adults, RCT, n = 82	TRF (early versus late)	(Xie et al. 2022)
		Yes	↓ weight	Healthy adults, RCT, n = 185	CR	(Kraus et al. 2019)
		Yes	↓ weight, BMI	Alzheimer’s patients, RCT/X, n = 21	KD	(Phillips et al. 2021)
↑ cardiometabolic health e.g. ↓ blood pressure, ↑ cardiac vascularity	CR – mouse, rat (Niemann et al. 2022); FMD – mouse, female (Mishra et al. 2021); TF – mouse, wild type and Fgf21-/-^# (Kawakami et al. 2022); TRF – mouse, hypertension models (Sims et al. 2022) ^# 24 h one-off fast	Yes	↓ blood pressure	Healthy adults, RT, n = 16	FMD	(Wei et al. 2017)
		Yes	↓ systolic and diastolic blood pressure, ↔ arterial stiffness	Men with prediabetes, RT, n = 16	TRF (early)	(Sutton et al. 2018)
		Yes	↓ systolic and diastolic blood pressure	Healthy adults, RCT, n = 185	CR	(Kraus et al. 2019)
Aging and aging-associated pathology
↓ neurodegeneration e.g. ↑ cognitive function, ↓ amyloid pathology	CR – mouse, female (Qin et al. 2006); FMD – mouse, female (Brandhorst et al. 2015); IF – mouse (Li, Wang, and Zuo 2013); KD – mouse, Alzheimer’s model (Auwera et al. 2005; Xu et al. 2022); rat, Parkinson’s model, male (Kuter et al. 2021); TRF – mouse, chronic cerebral hypoperfusion model, male (Selvaraji et al. 2022)	Yes	↑ cognitive subscale	Alzheimer’s disease patients, BCS, n = 10	KD	(Taylor et al. 2018)
		Yes	↑ scale improvement for daily living activities and Addenbrookes Cognitive Examination	Alzheimer’s disease patients, RCT/X, n = 21	KD	(Phillips et al. 2021)
		Yes	↑ cognitive function (digit span test, Trail-Making Test B, and the global score)	Elderly non-demented individuals, BCT, n = 19	KD	(Ota et al. 2016)
↓ senolytic cell burden	Senolytic treatment with dasatinib & quercetin (Thadathil et al. 2022)	Yes	↓ senescent cell burden in adipose tissue and skin ↓ IL-1α, IL-6, MMP-9 and −12	Patients with diabetic kidney disease, BCS, n = 9	Senolytic (Dasatinib + Quercetin)	(Hickson et al. 2019)
↑ lifespan, ↓ non-neurodenegerative age-related disease and cancer*	ADF – mouse, age-associated lymphoma model (Descamps et al. 2005); CR – Rhesus monkey, aging-related death (Colman et al. 2009); Rhesus monkey, cancer incidence (Mattison et al. 2017); mouse (Pak et al. 2021); mouse, male (Acosta-Rodríguez et al. 2022); mouse, breast cancer model; (Rogozina et al. 2011); Drosophila melanogaster (Catterson et al. 2018); DR – Caenorhabditis elegans (Lee et al. 2006); FMD – mouse, female (Brandhorst et al. 2015); KD – mouse, male (Roberts et al. 2017); mouse (Dmitrieva-Posocco et al. 2022; Yu et al. 2020); TRF – Drosophila melanogaster (Ulgherait et al. 2021)	Yes / ?	↑ lifespan	Epidemiological observation, adults aged 65+	CR (Okinawa diet)	(Willcox et al. 2007)
		Yes / ?	↑ mortality and cardiovascular disease with increasing carbohydrate intake ↓ mortality and cardiovascular disease with increasing total fat intake	Prospective observational cohort study, n = 135,355	Observation of dietary intake of carbohydrates and fat (KD-like diets)	(Dehghan et al. 2017)

* No major RCT studies with dietary intervention and mortality or disease outcome in humans so far. This is likely not feasible (require large n, long follow-up, long-term compliance required), or at least difficult to achieve in practice, and may be challenging ethically.

Overview of molecular, metabolic, cellular, clinical, and longevity/disease findings that could be reproduced (or not) between animal models and human studies so far.

Abbreviations: n/a, not applicable; n/s, not studied; ADF: alternate-day fasting; BCS: baseline-controlled study; CC, case-control study (intervention versus control); CTRL: control; CR: caloric restriction; LFD: low fat diet; FMD: fasting-mimicking diet; IF: intermittent fasting; KD: ketogenic diet; NR: non-randomized; PF: periodic fasting; RCT: randomized controlled trial; RT: randomized trial; RCT/X: randomized controlled trial with crossover; VLCKD: very low carbohydrate ketogenic diet.

Signs: ↑: increase/improvement; ↓: decrease/attenuation; ↔: no effect.

Figure 1. Schematic overview of involvement of senescent cells in aging and how DR may aid disease prevention or treatment and increase healthspan. Abbreviations: SASP, senescence-associated secretory phenotype; DNAme: DNA methylation; ROS: reactive oxygen species.

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