Table 3.

The roles of GLP-1 RAs in aging-related diseases in animal models.

Agents	Models	Diseases	Dosing	Duration	Effects	Ref.
GLP-1	Wistar rats	T2DM	1.5 pmol/kg/min, s.c.	48 h	GLP-1 treatment can increase pancreatic insulin, GLUT2, and glucokinase mRNA in the old rats.	[44]
GLP-1	Wistar rats	T2DM	0.05, 0.1, 0.2, 0.4, 0.5 nmol/kg, IVGTT	-5, 0, 2, 4, 7, 10, 15, 20, 30 min	GLP-1 restores the acute insulin response to glucose and increases the clearance of glucose in the old animals.	[45]
GLP-1	Normal male mice	T2DM	25 nmol/kg/day, i.p.	12 d	GLP-1 counters aspects of the age-related impairment of pancreatic β-cell function and insulin sensitivity.	[46]
GLP-1	Wistar rats	T2DM	1.5 pmol/kg/min, s.c.	2 or 5 d	GLP-1 causes an up-regulation of PDX-1 expression in islets and total pancreas, induces pancreatic cell proliferation, and β-cell neogenesis.	[47]
exendin-4	NSG mice	T2DM	24 nmol/kg/day, s.c.	/	Exendin-4 stimulates insulin secretion by both juvenile and adult human β cells.	[48]
GLP-1	Adult male rats	Obesity	/	/	Intracerebroventricular (ICV) GLP-1 powerfully inhibits feeding in fasted rats.	[61]
exenatide	C57BL/6J mice	Obesity	24 nmol/kg, i.p.	8 w	Exenatide promotes brown remodelling of WAT in a SIRT1-dependent manner.	[66]
GLP-1 liraglutide exenatide	CD-1 mice, SD rats, cynomolgus monkeys	OP	/	/	GLP-1 RAs stimulate calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rodents.	[78]
liraglutide	SAMP8 mice	AD	100 or 500 g/kg/day, s.c.	4 m	Liraglutide delays the progressive decline in memory function associated with hippocampal neuronal loss.	[86]
liraglutide	APP/PS1 mice	AD	25 nmol/kg	8 w	Liraglutide reduces inflammation response, β-amyloid plaque count, dense-core plaque numbers, soluble amyloid oligomers levels, prevents memory impairments, synapse loss and deterioration of synaptic plasticity, and increases young neurons numbers.	[87]
liraglutide	APP/PS1 mice	AD	25 nmol/kg, i.p.	2 m	Liraglutide can reverse some of the key pathological hallmarks of AD and prevents the progression of it.	[88]
exendin-4	3xTg-AD mice	AD	3.5 pM/kg/min, s.c.	16w	Exendin-4 reduces brain levels of tau, Aβ protein precursor and Aβ in STZ 3xTg-AD mice.	[89]
liraglutide lixisenatide	C57/BL6 mice	PD	2.5, 25, 250 nmol/kg, i.p./ lixisenatide (25 nmol/kg, i.p.)	5min,30min,3h/ 3week	Liraglutide and lixisenatide can cross the BBB and enhance neurogenesis.	[97]
NLY01	C57BL6, hA53T α-synuclein transgenic, TLR-2 KO mice	PD	3 mg/kg s.c., twice weekly	/	NLY01 exerts neuroprotective effects via the direct prevention of microglial mediated conversion of astrocytes to an A1 neurotoxic phenotype.	[98]
exenatide	ApoE-/-mice	Vascular aging	5 µg/kg s.c., twice daily	12w	Exenatide ameliorated vascular aging induced by high-fat diet.	[106]
exenatide	C57BL/6J mice	Vascular aging	5 μg/kg/day, s.c.	14d	Exenatide prevents vascular senescence.	[108]
liraglutide	ApoE-/-mice	Atherosclerosis	300 µg/kg, s.c. twice daily	4w	Liraglutide inhibits progression of atherosclerotic plaque formation and enhances plaque stability.	[113]
liraglutide	ApoE-/- mice	Atherosclerosis	0.4 mg/kg/day, s.c.	9w	Liraglutide ameliorates atherogenesis through reducing serum AGEs levels and RAGE.	[114]
exendin-4	C57BL/6J mice	Atherosclerosis	300 pmol/kg/day 24 nmol/kg/day, s.c.	28d	Exendin-4 reduces monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages.	[116]
liraglutide	ApoE-/- mice	Atherosclerosis	300 μg/kg/day, s.c.	6 or 4 w	Liraglutide regulates immune cell phenotypes in early and preestablished atherosclerosis.	[117, 118]
lixisenatide liraglutide	Apoe -/-Irs2 +/- mice	Atherosclerosis	lixisenatide (10 μg/kg/day, s.c) liraglutide (400 μg/kg/day, s.c)	1 m	Lixisenatide decreases atheroma plaque size and instability by reprogramming macrophages towards an M2 phenotype.	[119]
liraglutide	ApoE-/-mice	Atherosclerosis	400 μg/day, s.c.	4 w	Liraglutide suppresses atherosclerotic lesions and increases AMPK phosphorylation in the aortic wall.	[120]
GLP-1	SD rats	Hypertension	30 pmol/kg/min, IVGTT	120 or 30min	GLP-1 acutely recruits microvasculature and increases basal glucose uptake in muscle via a NO-dependent mechanism	[129]
liraglutide	C57BL/6 mice	Hypertension	27or30 μg/kg, i.p. twice daily	/	Liraglutide promotes vasorelaxation by inducing the secretion of ANP.	[130]
GLP-1	Wistar rats	Hypertension	1 μg/kg·min, i.p.	60min	GLP-1 can exert direct effects on relaxing rat conduit arteries, independently of NO and the endothelium.	[133]
liraglutide	SHR, WKY rats	Hypertension	0.9?µg/3?µl/day, i.v.	15d	Liraglutide attenuates the progression of hypertension in SHR through activating brainstem DBH neurons and suppressing sympathetic nerve activity.	[136]
liraglutide	STZ diabetic rats	Kidney diseases	0.3 mg/kg/12 h, s.c.	4w	Liraglutide against oxidative stress and diabetic nephropathy via a PKA-mediated inhibition of renal NAD(P)H oxidase.	[12]
liraglutide	Wistar rats	OA	50?μg/kg/day, s.c.	28d	Liraglutide ameliorates inflammation through the activation of the PKA/CREB pathway in OA rats.	[165]
liraglutide	SD rats	Sarcopenia	200µg/kg, s.c. twice daily	/	Liraglutide ameliorates skeletal muscle atrophy in rodents.	[168]
exendin-4 dulaglutide	C57BL/6, DBA/2J-mdx mice	Sarcopenia	exendin-4 (100 ng/day, s.c.) dulaglutide (1 mg/kg/week, s.c)	exendin-4(8w) dulaglutide(3w)	GLP-1 RAs ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors.	[169]

AGEs: advanced glycation end products; DBH: dopamine beta-hydroxylase; MSTN: myostatin; OA: osteoarthritis; OP: osteoporosis; RAGE: receptor for advanced glycation end products; SD: Sprague-Dawley; SHR: spontaneously hypertensive rats; STZ: streptozotocin; WAT: white adipose tissue; WKY: Wister Kyoto rats