Table 1.

Roles of spermidine in aged-related diseases.

	Disease	Functions	Potential mechanisms
Cardiovascular Diseases	CAD	regulate myocardial ischemic reperfusion	modulate arterial blood perfusion [92]
	CAD	inhibit AS	decrease inflammatory cytokines and improving mitochondrial function [94]
	CAD	reduce AS	induce autophagy [95, 96]
	CAD	attenuate AS	antagonize platelet aggregation [96]
	CAD	protect from AS	promote conversion of PHBP [97]
	CAD	inhibit AS	activate eNOS [98]
	EH	inhibit EH	regulate NMDA and its receptors [100]
	EH	reduce blood pressure	improve age-related diastolic [101]
	EH	inhibit EH	regulate angiotensin II [103]
	HF	delay HF	prevent cardiac hypertrophy and protect cardiomyocytes [15, 101]
	HF	attenuate HF	attenuate mitochondrial dysfunction [105]
	HF	protect cardiac	reduce telomere attrition [106]
	HF	protect cardiac	regulate apoptosis of myocardial ischemic cells [107]
Neurodegenerative Diseases	AD	reduce memory decline	induce autophagy [110, 111]
	AD	ameliorate dementia	prevent inflammation and apoptosis of nerve cells [44]
	AD	influence memory	stimulate neural actions [112]
	PD	protect from PD	maintain the mitochondria in dopaminergic neurons function [113]
	PD	protect against PD	induce autophagy [114]
	PD	protect against PD	trigger PINK1-PDR1-dependent mitophagy [115]
	PD	alleviate PD	inhibit α-synuclein and promote climbing activity [116, 117]
	PD	protect against PD	exert anti-inflammatory and antioxidant properties [118]
	PD	attenuate PD	regulate SAT1 activity [119]
Metabolic Diseases	T2DM	prevent T2DM	improve insulin sensitivity and maintain glucose homeostasis [120]
	T2DM	prevent T2DM	promote facultative cell proliferation and maintain glucose homeostasis [121]
	T2DM	prevent diabetic complications	inhibit lipid peroxidation, hemoglobin glycation [122]
	T2DM	reduce hyperglycemic	enhance glucose utilization [123]
	T2DM	reduce nephropathy complications	reduce renal collagen [125]
	Obesity	ameliorate obesity	reduce adiposity and hepatic fat accumulation [120]
	Obesity	loss of weight	regulate lipid metabolism, inflammatory response, and thermogenesis [70]
	Obesity	attenuate obesity	induce autophagy in white adipose tissue [126]
	Obesity	alleviate obesity	enhance intestinal barrier function and alternate microbiota composition [127]
	Obesity	reduce adiposity	inhibit lipogenic genes expression [69]
	Obesity	attenuate obesity	increase energy expenditure [128]
	Metabolic syndrome	correct metabolic syndrome	activate TETA [129]
	Metabolic syndrome	inhibit metabolic syndrome	ameliorate hepatic steatosis and adipose tissue inflammation [70]
Musculoskeletal Diseases	Osteoporosis	enhance bone strength	promote warmth regeneration [130]
	Osteoporosis	prevent bone loss	disturb osteoclastic activation [131, 132]
	Osteoporosis	reduce migration and osteoclastogensis	inhibit RANKLE-mediated signaling pathway, prevent transcription factors [133]
	Sarcopenia	ameliorate skeletal muscle atrophy	regulate skeletal muscle differentiation [54]
	Sarcopenia	ameliorate muscle defects	induce autophagy [135]
	Osteoarthritis	improve osteoarthritis	activate autophagy [136]
	Osteoarthritis	alleviate synovitis, osteophyte formation and cartilage degeneration	inhibit TNF-α induced NF-κB/p65 signaling pathway [137]
	Osteoarthritis	protect chondrocytes	reduce oxidant and inflammatory responses [138]
Immune Diseases	influenza	improve CD8+ T cell responses	induce autophagy [140]
	cytomegalovirus infection	improve CD8+ T cell responses	induce autophagy [140]
	colitis	attenuate pathology	promote homeostasis differentiation of regulatory T cells [138]
	IBD	attenuate inflammation	induce autophagy [141]

CAD: coronary artery disease; AS: atherosclerosis; EH: essential hypertension; HF: heart failure; AD: Alzheimer's disease; PD: Parkinson’s disease; T2DM: type 2 diabetes mellitus; PHBP: plasma hyaluronan-binding protein; eNOS: endothelial nitric oxide synthase; NMDA: N-methyl-D-aspartate; SAT1: Spermidine/spermine N1-acetyltransferase; TETA: Triethylenetetramine dihydrochloride; TNF-α: tumor necrosis factor-α; NF-κB: nuclear factor kappa-B