Table 1.

Mitokines in mammals

Mitokine name	Stress/expression inducers	Effects on cellular pathways and metabolism	Effects on aging
FGF21	Generally, acts as an anti-inflammatory factor in metabolism-related diseases Increased expression due to mitochondrial dysfunction	Sends signals non-autonomously to distal cells to reduce energy metabolism for non-essential functions Increases insulin sensitivity and thermogenesis in response to hepatic mitochondrial dysfunction Increases glucose catabolism in liver tissue	With the expression of aging-related genes, has the ability to delay cellular aging
GDF15	Increased expression to help prevent diet-induced hepatic steatosis and to regulate body fat Secreted to combat the inflammation associated with obesity-associated lysosomal stress	Suppresses organismal food and energy intake Increases the expression of certain hepatic enzymes to increase glucose catabolism and fatty acid metabolism. Decreases gene sets responsible for steroid hormone biosynthesis and lipid metabolism (allocating cellular energy towards more necessary mechanisms).	One of the most upregulated proteins in response to age-related disease and aging Serves protective roles for many tissues in response to stress and aging
MOTS-c	Induced by exercise in humans In mice, MOTS-c levels decrease after cold treatment In vitro, MOTS-c levels increase after glucose restriction, serum deprivation, and oxidative stress	Activates AMPK to improve energy metabolism and prevents DIO and insulin resistance Reduces visceral fat accumulation and hepatic steatosis in high-fat diet-fed mice Inhibits genes related to lipogenesis and increases glucose uptake, glucose utilization, fatty acid oxidation, and oxidative respiration Suppresses inflammation	Circulating levels decrease with age The m.1382A>C polymorphism of MOTS-c is associated with longevity in the Japanese population Protects against aging-related diseases by increasing senescence-associated secretory phenotypes
Humanin (HN)	In patients with Alzheimer’s disease, the serum level of HN is decreased. Reduced by insulin growth factor 1 and growth hormone	Has anti-apoptosis, anti-oxidation, anti- inflammatory, cytoprotective, and neuroprotective effects Protects against inflammation-related diseases, such as Alzheimer’s disease, type 2 d Diabetes, cardiovascular disease, and atherosclerosis	Conflicting literature on whether the level of HN increases [37, 38] or decreases [39,40] with age Treatment of HN protects against age-related diseases Children of centenarians have higher HN than age-matched controls
Small Humanin-Like Peptides (SHLPs)	The inducer of SHLPs has yet to be investigated	Reduces apoptosis, decreases generation of ROS, improves mitochondrial metabolism, increases glucose uptake, suppresses hepatic glucose production, regulates leptin levels, and increases cell viability	May preserve mitochondrial function during aging and induces exercise-like adaptations Circulating levels decrease with age Protects against age-related diseases, such as Alzheimer’s disease
ADM2	Induced by mitochondrial stress and ATF4	Inhibits obesity-induced insulin resistance in mice	ADM levels are elevated in aged human brain ADM levels are decreased as mice age ADM knockout mice show better memory preservation during aging [41]
ANGPTL6	Induced by Crif1 knockout Induced by OXPHOS dysfunction Induced by treatment with rotenone and oligomycin	Increases insulin sensitivity, glucose tolerance, and energy expenditure, and reduces body weight in mice Serum levels increase in patients with metabolic disease, potentially due to over-compensation Serum levels are reduced after adopting routine exercise	ANGPTL6’s effect on aging remains to be studied