Irisin enhances longevity by boosting SIRT1, AMPK, autophagy and telomerase

Probably not a substantial claim: may not pass S3 (load-bearing).

In some tissues, such as bone and fat, irisin acts via αV/β5 integrin receptors.

“In some tissues, such as bone and fat, irisin acts via αV/β5 integrin receptors (Ref. 6).”

• cites Ref. 6Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Irisin is secreted in white adipose tissue (WAT), mainly in subcutaneous adipose tissue (SAT) adipocytes and at a lower extent in visceral adipose tissue adipocytes, with expression increasing during physical activity.

“Irisin is also secreted in white adipose tissue (WAT), so it may also behave as an ‘adipokine’. Regarding this tissue, it has been observed that in rodents irisin is secreted mainly in subcutaneous adipose tissue (SAT) adipocytes and, at a lower extent, in visceral adipose tissue adipocytes, with expression increasing when performing physical activity (Ref. 10).”

• cites Ref. 10Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Irisin is a myokine, expressed, produced and released by muscle fibres, exerting effects on other organs.

“Irisin is considered as a ‘myokine’, term that refers to cytokines or other peptides that are expressed, produced and released by muscle fibres exerting their effects on other organs of the body (Ref. 7).”

• cites Ref. 7Not checked yet

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The αV integrin complex is probably the main irisin receptor, but other irisin receptors within or outside the integrin family are not excluded.

“Therefore, these data suggest that the αV integrin complex is probably the main irisin receptor; however, it is important to note that this does not exclude the possibility of other irisin receptors within or outside the integrin family.”

• cites Ref. 5Not checked yet

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Irisin is a polypeptide hormone consisting of 112 amino acids with an approximate molecular weight of 12 kDa, 100% conserved in human, mouse and rat, discovered by Boström et al. in 2012.

“Irisin is a polypeptide hormone consisting of 112 amino acids with an approximate molecular weight of 12 000 Daltons (Da; 12 kDa) 100% conserved in human, mouse and rat, discovered by Boström et al. in 2012 (Ref. 4)”

• cites Ref. 4Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Irisin is present in several human tissues including testicles, pancreas, spleen, brain and stomach, and also in salivary glands, skin, liver, kidney and heart muscle; cardiac muscle produces more irisin than skeletal muscle.

“This analysis also revealed the presence of irisin in several human tissues such as testicles, pancreas, spleen, brain and stomach (Ref. 8). Also, it was previously shown that irisin is expressed in salivary glands, skin, liver, kidney and heart muscle, and, interestingly, the authors conclude that cardiac muscle produces more irisin than skeletal muscle (Ref. 9).”

• cites Ref. 8Not checked yet

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• cites Ref. 9Not checked yet

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Irisin-supplemented media from astrocytes decreased β-amyloid toxicity and decreased levels of proinflammatory cytokines (IL-6, IL-1β and COX-2).

“In vitro studies showed that irisin-supplemented media from astrocytes decreased β-amyloid toxicity also decreased the levels of proinflammatory cytokines (IL-6, IL-1β and cyclooxygenase-2 (COX-2)) (Ref. 37).”

• cites Ref. 37Not checked yet

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Serum irisin levels were upregulated in ALS patients, while in animal models with mutant SOD1, levels of irisin and myostatin were downregulated.

“Some authors showed that serum irisin levels were upregulated in ALS patients (Ref. 48), meanwhile in animal models with mutant SOD1, levels of irisin and myostatin have found downregulated (Ref. 49).”

• cites Ref. 48Not checked yet

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• cites Ref. 49Not checked yet

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Decreasing the levels of irisin in mice brain impairs cognitive behaviour, which is restored by increasing the peripheral expression of irisin.

“These authors showed how decreasing the levels of irisin in mice brain impairs cognitive behaviour that were restored by increasing the peripheral expression of irisin (Ref. 36).”

• cites Ref. 36Not checked yet

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No differences were found between genotypic/allelic frequencies of two FNDC5 SNPs in centenarians versus controls, nor a significant association between the two SNPs and successful disease-free longevity.

“However, no differences were found between the genotypic/allelic frequencies of the two SNPs in centenarians versus controls in either population, nor a significant association between the two SNPs and successful disease-free longevity (Ref. 14).”

• cites Ref. 14Not checked yet

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Ampelopsin attenuates skeletal muscle atrophy through activating AMPK/SIRT1/PGC-1α signalling cascade in rats.

“Similar effects have been found in rats treated with the flavonoid ampelopsin which attenuates the atrophy of skeletal muscle through activating AMPK/SIRT1/PGC-1α signalling cascade (Ref. 59).”

• cites Ref. 59Not checked yet

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In an MPTP animal model of PD, rats treated with irisin and bone marrow stromal cells prevented dopaminergic neuron loss, and irisin facilitated the stem cells with regenerative ability inducing migration of BMSCs in the damaged brain area.

“In an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), animal model of PD, authors showed that rats treated with irisin and bone marrow stromal cells (BMSCs) prevented the dopaminergic neurons loss and irisin facilitated the stem cells with regenerative ability inducing the migration of BMSCs in the damaged brain area (Ref. 45).”

• cites Ref. 45Not checked yet

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In human skeletal muscle cells treated with irisin, intracellular ATP significantly decreased after 1 h, coinciding with an increase in AMPK phosphorylation.

“The researchers measured intracellular ATP in human skeletal muscle cells treated with irisin and found a significant decrease in the levels of this molecule after 1 h, this decline coincided with the increase in AMPK phosphorylation.”

• cites Ref. 15Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Injected recombinant irisin has a short half-life (1 h) in mice.

“In relation to the pharmacokinetics of irisin, a short half-life (1 h) of injected recombinant irisin in mice has been reported (Ref. 6)”

• cites Ref. 6Not checked yet

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Skeletal muscle AMPK is necessary to maintain basal FNDC5 expression; AMPK gene knockout mice showed a drastic decrease in FNDC5 expression compared with wild-type mice.

“Another research group concluded that skeletal muscle AMPK is necessary to maintain basal FNDC5 expression, by comparing AMPK gene knockout mice with wild-type mice and observing a drastic decrease in FNDC5 expression in the first group of mice.”

• cites Ref. 57Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

AMPK is activated when energy levels are low, influencing physiological processes to increase energy production and coordinate a decrease in ATP expenditure.

“AMPK is a highly conserved enzyme in the eukaryotic kingdom that is activated when energy levels are low, influencing a wide range of physiological processes with the purpose to increase energy production and coordinate a decrease in the expenditure of adenosine triphosphate (ATP).”

• cites Ref. 55Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Exercise improves memory, attention and neuronal plasticity even in elderly patients, being a non-pharmacological approach to prevent brain ageing vulnerable to AD, PD and stroke.

“It has been reported that exercise is involved in many physiological processes at the central nervous system that may improve memory, attention and promoting neuronal plasticity even in elderly patients, being a non-pharmacological approach to prevent the brain ageing vulnerable to AD, PD and stroke (Ref. 29).”

• cites Ref. 29Not checked yet

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FNDC5/irisin acts through MAPK signalling pathways in neural differentiation, endothelial cell proliferation, and osteoblast proliferation and differentiation, preventing bone loss by p38 and ERK activation.

“Recent studies have shown that FNDC5/irisin acts through MAPK signalling pathways in numerous cellular processes, such as neural differentiation, endothelial cell proliferation as well as osteoblast proliferation and differentiation (Refs 25, 27) preventing bone loss by p38 and ERK activation (Ref. 28) (Fig. 2).”

• cites Refs 25, 27Not checked yet

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• cites Ref. 28Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Irisin released in the blood stream by muscle can reach the brain inducing BDNF expression.

“Some authors suggest that irisin released in the blood stream by the muscle can reach the brain inducing BDNF expression (Ref. 31).”

• cites Ref. 31Not checked yet

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The AMPK pathway is involved in PGC-1α/FNDC5 and irisin expression, as icariin enhances dose-dependent phosphorylation of AMPK and increases mRNA levels of irisin/FNDC5 in C2C12 myocytes and decreases body weight gain in mice.

“Moreover, a study demonstrated that AMPK pathway is involved in the PGC-1α/FNDC5 and irisin expression using a flavonoid, icariin, which enhances dose-dependent phosphorylation of AMPK protein and increased mRNA levels of irisin/FNDC5 in C2C12 myocytes and decreased body weight gain in mice (Ref. 58).”

• cites Ref. 58Not checked yet

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Classified as probably not a substantial claim. May combine two claims.

AMPK, sirtuin pathways, autophagy and telomere length are well-studied pathways that regulate ageing, and their modulation influences the rate of ageing.

“Among others these include four well-studied pathways that are known to regulate ageing, and whose modulation has been shown to influence the rate of ageing, these are AMPK, and sirtuin pathways, autophagy and telomere length (TL) (Refs 51, 52, 53, 54).”

• cites Refs 51, 52, 53, 54Not checked yet

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Irisin activates the cAMP-PKA-CREB pathway, which participates in neural differentiation and neuroprotection.

“and activate cAMP–protein kinase A (PKA)–cAMP response element-binding (CREB) pathway, which has been shown to participate in neural differentiation and neuroprotection (Ref. 35).”

• cites Ref. 35Not checked yet

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Irisin prevented the loss of dopamine neurons and striatal dopamine levels in an α-synuclein preformed fibrils-induced model of PD, and irisin promotes endolysosomal degradation of pathological α-syn.

“Irisin also prevented the loss of dopamine neurons and striatal dopamine levels in an α-synuclein preformed fibrils (α-syn PFF)-induced model of PD. The authors suggested that irisin promotes the endolysosomal degradation of pathological α-syn (Ref. 47).”

• cites Ref. 47Not checked yet

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In wild-type mice, AMPK phosphorylation is increased immediately when muscle contraction occurs, an effect abolished in knockout mice.

“Likewise, in wild-type mice, AMPK phosphorylation is increased immediately when muscle contraction occurs, an effect that was abolished in knockout mice (Ref. 57).”

• cites Ref. 57Not checked yet

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At the systemic level, irisin maintains glucose and lipid homeostasis, which is crucial in treatment for type 2 diabetes mellitus, obesity or other metabolic diseases.

“At the systemic level, irisin maintains glucose and lipids homoeostasis which is crucial in treatment for type 2 diabetes mellitus (T2DM), obesity or other metabolic diseases (Ref. 26).”

• cites Ref. 26Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Irisin can bind a specific domain between β- and α-secretase cleavage sites of amyloid precursor protein, reducing the formation of both Aβ40 and Aβ42 peptides.

“Some authors suggest that irisin can bind a specific domain between β- and α-secretase cleavage sites of amyloid precursor protein (APP) reducing the amyloid beta-peptide (Aβ) formation of both Aβ40 and Aβ42 peptides (Ref. 38).”

• cites Ref. 38Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Basal irisin is higher in young adults than in older adults; circulating irisin increases immediately after high-intensity interval exercise but not in chronic exercise; exercise-induced irisin secretion is independent of age or fitness level.

“Another study revealed that basal irisin was higher in young adults than in older adults and that circulating irisin increased immediately after high-intensity interval exercise, but not in chronic exercise, and this exercise-induced irisin secretion was independent of age or fitness level (Ref. 15).”

• cites Ref. 15Not checked yet

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Irisin functions as a muscle-derived molecule that communicates directly with adipose tissue, acting as a thermogenic protein by increasing UCP-1 levels and promoting WAT browning.

“Therefore, irisin functions as a muscle-derived molecule that communicates directly with adipose tissue acting as a thermogenic protein by increasing UCP-1 levels and promoting WAT browning.”

• cites Ref. 4Not checked yet

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The hepatobiliary and renal systems act together to excrete irisin; after intravenous injection of 125I-irisin in mice, irisin levels were observed in gallbladder, liver and kidneys at 15 min and decreased between 30 and 120 min.

“The administration of irisin in vivo in rodents revealed that the hepatobiliary and renal systems act together to guarantee the correct excretion of the hormone. In this experiment, 125I-irisin was tracked in mice after intravenous injection using single-photon emission computed tomography and, 15 min after the injection, irisin levels were observed in the gallbladder, liver and kidneys, decre”

• cites Ref. 16Not checked yet

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Irisin allows crosstalk between muscle and other organs, including adipose tissue, bone, brain, liver, pancreas, vascular bed, heart and brain, as well as communication within the muscle itself.

“Irisin, as a hormone, allows a crosstalk between the muscle and other organs, including adipose tissue, bone, brain, liver, pancreas, vascular bed, heart and brain, as well as communication within the muscle itself (Ref. 18).”

• cites Ref. 18Not checked yet

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SIRT1 deacetylates PGC1-α, activating it, which leads to regulation of mitochondrial gene expression and an increase in PGC1-α activity that, in muscle, results in an increase in circulating irisin.

“SIRT1 is of great interest in this study since one of its non-histone targets is PGC1-α, which undergoes reversible acetylation/deacetylation control; when deacetylated by SIRT1, PGC1-α is activated, which leads to the regulation of subsequent pathways involved in the control of mitochondrial gene expression and the increase in activity of PGC1-α that, in muscle, results in an increase in circul”

• cites Ref. 68Not checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

SIRT1 is one of the gatekeepers that control the activity of PGC1-α, and together they determine an essential link in the regulatory network of metabolic homoeostasis.

“In conclusion, the metabolic sensor SIRT1 is one of the gatekeepers that control the activity of PGC1-α, and together they determine an essential link in the regulatory network of metabolic homoeostasis.”

May combine two claims.

Metformin can promote up-regulating irisin expression in mice muscle and in INS-1E cells in a high-glucose environment through the AMPK/SIRT1/PGC-1α signal pathway, improving its function and survival.

“Thus, metformin, a widely used drug of T2DM that improves insulin sensitivity and inhibits hepatic gluconeogenesis (Ref. 75), can promote up-regulating irisin expression in mice muscle (Ref. 76) and in INS-1E cells in high-glucose environment through AMPK/SIRT1/PGC-1α signal pathway, improving its function and survival (Ref. 77).”

• cites Ref. 76Not checked yet

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• cites Ref. 77Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The rate of telomere shortening can increase or decrease under influence of lifestyle, so correct diet and physical exercise can reduce the rate of shortening or at least prevent excessive telomere wear.

“The rate of telomere shortening can increase or decrease under the influence of lifestyle, so that a correct diet and physical exercise can reduce the rate of shortening or at least prevent excessive telomere wear (Ref. 94).”

• cites Ref. 94Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

SIRT or sirtuins are a family of NAD+ dependent proteins, initially identified as class III histone deacetylases.

“SIRT or sirtuins are a family of NAD+ dependent proteins, which were initially identified as class III histone deacetylases (Ref. 67).”

• cites Ref. 67Not checked yet

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In spontaneously hypertensive rats, irisin injection reduced blood pressure through the AMPK-Akt-eNOS-NO signalling pathway, increasing the release of NO.

“At the vascular level, in spontaneously hypertensive rats, it was shown that irisin injection reduced blood pressure through the AMPKAkt–endothelial NO synthase (eNOS)–nitric oxide (NO) signalling pathway, increasing the release of NO (Ref. 63).”

• cites Ref. 63Not checked yet

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In an animal model for acute lung injury, irisin pretreatment significantly augmented the ratio of p-AMPK/AMPK protein and up-regulated the expression of SIRT1 protein in lung tissue, improving alveolar epithelial barrier dysfunction.

“In this regard, in experiments with an animal model for acute lung injury irisin pretreatment not only significantly augmented the ratio of p-AMPK/AMPK protein, but also up-regulated the expression of SIRT1 protein in lung tissue improving the alveolar epithelial barrier dysfunction (Ref. 72).”

• cites Ref. 72Not checked yet

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In soleus muscle tissue of diabetic rats trained by running on a treadmill for 12 weeks, there was a significant increase in irisin and sirtuin-1 mRNA expression, which can be a compensatory mechanism for reducing oxidative stress and improving symptoms in diabetics.

“Moreover, irisin and sirtuin-1 mRNA were investigated in the soleus muscle tissue of diabetic rats that were trained by running on a treadmill for 12 weeks. The researchers found a significant increase in the expression of these genes, which can be a compensatory mechanism for reducing oxidative stress and improving the symptoms in diabetics (Ref. 73).”

• cites Ref. 73Not checked yet

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mTOR is the primary inhibitor of autophagy in both animal models and humans; IGF-1 signals through IGF1-R to activate mTOR and inhibit autophagy.

“In contrast, mTOR is the primary inhibitor of autophagy in both animal models and humans; IGF-1 signals through its IGF1-R receptor that activates mTOR to inhibit autophagy.”

May combine two claims.

Exogenous irisin increased LC3-II and decreased p62 in hypertrophic heart models, indicating irisin promotes autophagy and autophagic flow protecting against pressure overload-induced cardiac hypertrophy.

“In this experiment, markers LC3-II (number of autophagosomes) and p62 (protein that is degraded in the process and serves to determine autophagic flow) were measured; the supply of exogenous irisin increased the levels of LC3-II and decreased those of p62, that is, irisin promotes autophagy and autophagic flow protecting against pressure overload-induced cardiac hypertrophy (Ref. 89).”

• cites Ref. 89Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Autophagy is a highly conserved catabolic process in eukaryotes activated under nutrient scarcity, resulting in renewal of cytoplasmic material and mobilisation of macromolecules to generate energetic compounds.

“Autophagy is a highly conserved catabolic process in eukaryotes that is activated under conditions of nutrient scarcity, and results in the renewal of cytoplasmic material as well as the mobilisation of macromolecules to generate highly energetic compounds that cover cellular demands under conditions of decreased internal or external resources (Ref. 83).”

• cites Ref. 83Not checked yet

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In cardiomyocytes with Ang-II-induced hypertrophic damage, Ang-II increased LC3-II and p62, indicating increased autophagy but flow blockage.

“Ang-II increased the levels of LC3-II and p62, which indicates an increase in the level of autophagy but a flow blockage, that is, although there is an increase in autophagy, the process is failing by not being resolved appropriately.”

• cites Ref. 91Not checked yet

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All neurodegenerative diseases share certain pathogenic mechanisms, including age-associated autophagic flux imbalance that causes an inability to remove neurotoxic oligomers or misfolded proteins.

“All neurodegenerative diseases share certain pathogenic mechanisms, including age-associated autophagic flux imbalance that causes an inability to remove neurotoxic oligomers or misfolded proteins (Ref. 84).”

• cites Ref. 84Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

SIRT1 is expressed mainly in the nucleus, although under certain specific conditions it can act on cytosolic proteins.

“Within this family, the most studied enzyme is SIRT1, a protein that is expressed mainly in the nucleus, although under certain specific conditions it can act on cytosolic proteins (Ref. 69).”

• cites Ref. 69Not checked yet

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A clinical trial with 90 men and women with type 2 diabetes and overweight/obesity who were supplemented with vitamin D showed a parallel significant increase in plasma levels of irisin and SIRT1, supporting the link between these two molecules, considering that SIRT1 stimulates PGC-α which in turn enhances irisin production.

“In the same sense, a clinical trial with 90 men and women with type 2 diabetes and overweight/obesity who were supplemented with vitamin D showed that there was a parallel significant increase in the plasma levels of irisin and SIRT1 supporting the link between these two molecules, considering that SIRT1 stimulates PGC-α which in turn enhances irisin production (Table 2).”

May combine two claims.

SIRT1/PGC1-α and FNDC5/irisin can potentiate each other, and this relationship could explain many of the protective effects related to physical activity.

“In fact, it seems that SIRT1/PGC1-α and FNDC5/irisin can potentiate each other and the relationship between them could explain many of the protective effects related to physical activity.”

May combine two claims.

Irisin is a key player during the ageing process and could be a novel target molecule for the therapeutic approach to boost longevity pathways.

“In conclusion, irisin is a key player during the ageing process and it could be a novel target molecule for the therapeutic approach to boost longevity pathways.”

• AssumptionRests on an assumption: The effects of irisin observed in animal and cell models are relevant to human ageing and longevity.
• AssumptionRests on an assumption: The association between high circulating irisin levels and disease-free longevity reflects a causal role of irisin in longevity.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Sirtuins are essential regulators of the control network of energy homeostasis and participate in a wide number of cellular processes such as glucose and fat metabolism, exerting their action on numerous nuclear transcriptional factors and on specific cytoplasmic and mitochondrial proteins.

“Later, it was discovered that they were essential regulators of the control network of energy homoeostasis and participated in a wide number of cellular processes (such as glucose and fat metabolism), exerting their action on numerous nuclear transcriptional factors and on specific cytoplasmic and mitochondrial proteins.”

• cites Ref. 68Not checked yet

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In hypertrophic heart models, irisin deficiency caused a decrease in autophagy and aggravated autophagic failure, whereas exogenous irisin induced autophagy and improved the process.

“Recently, studies with hypertrophic heart models comparing wild-type mice with FNDC5 knockout mice showed that irisin deficiency caused a decrease in autophagy and aggravated autophagic failure, whereas exogenous supply of irisin induced autophagy and improved the development of the process.”

• cites Ref. 89Not checked yet

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Resveratrol administered orally in mice and in humans determined an increase in the expression of FNDC5 and UCP-1 in SAT and improves the glycaemic and lipid profiles; SIRT1 is the candidate molecule mediating the relationship between resveratrol administration and the increase in FNDC5 and UCP-1.

“Resveratrol administered orally in mice and in humans determined an increase in the expression of FNDC5 and UCP-1 in SAT and improves the glycaemic and lipid profiles. In this study it was shown that the candidate molecule that would mediate the relationship between the administration of resveratrol and the increase in FNDC5 and UCP-1 would be SIRT1 (Ref. 79).”

• cites Ref. 79Not checked yet

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Autophagy promotes longevity in model organisms, and although this role is not fully established in mammals, an increase in autophagy is an effective mechanism to prevent premature ageing, improve health and promote longevity in mammals.

“Numerous studies show that autophagy promotes longevity in model organisms, and although this role is not fully established in mammals, it is known that an increase in autophagy is an effective mechanism to prevent premature ageing, improve health and promote longevity in mammals (Ref. 83).”

• cites Ref. 83Not checked yet

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Some beneficial effects of physical activity are related to autophagy induction in many tissues including muscle, adipose tissue, liver, pancreas, heart or brain.

“Some of the beneficial effect of physical activity seen to be related to autophagy induction in many tissues including muscle, adipose tissue, liver, pancreas, heart or brain (Refs 87, 88).”

• cites Refs 87, 88Not checked yet

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Exogenous irisin supplementation reduces p62 and increases LC3-II in Ang-II-treated cardiomyocytes, promoting increased autophagy and autophagic flux.

“Exogenous irisin supplementation reduces p62 levels and increases LC3-II levels, promoting increased autophagy and autophagic flux.”

• cites Ref. 91Not checked yet

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In old rats with hepatic ischaemia-reperfusion, exogenous recombinant irisin increased p62 and LC3BII proteins and autophagosomes, improving inflammation, oxidative stress, apoptosis and liver injury.

“Interestingly, hepatic ischaemia–reperfusion (IR) of old rats treated with exogenous recombinant irisin showed higher level of p62 and LC3BII proteins and higher amount of autophagosomes improving inflammation, oxidative stress, apoptosis and liver injury in an old rat model of hepatic IR (Ref. 93).”

• cites Ref. 93Not checked yet

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In Ang-II-treated cardiomyocytes, irisin increased both autophagosomes and autophagolysosomes, translating into correct functioning and resolution of the autophagic mechanism.

“Also, when applying irisin, an increase in both autophagosomes and autophagolysosomes was observed, which translates into correct functioning and resolution of the autophagic mechanism (Ref. 91).”

• cites Ref. 91Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Regulation of autophagy involves pro-ageing molecules mTOR and IGF-1, as well as anti-ageing molecules SIRT and AMPK.

“The regulation of autophagy involves pro-ageing molecules such as mTOR and insulin-like growth factor-1 (IGF-1), as well as anti-ageing molecules, such as SIRT and AMPK.”

May combine two claims.

In hypoxia-treated cardiomyocytes in vitro and infarcted hearts in vivo, irisin enhanced autophagy, favouring elimination of damaged mitochondria and protecting them from further damage following myocardial infarction, resulting in increased ATP levels in response to hypoxia.

“In studies on hypoxia-treated cardiomyocytes in vitro and on infarcted hearts in vivo irisin was capable to enhance autophagy favouring the elimination of the damaged mitochondria and protect them from further damage following myocardial infarction, resulting in an increase in ATP levels in response to hypoxia (Ref. 90).”

• cites Ref. 90Not checked yet

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C2C12 cells augmented the autophagic rate increasing LC3 and increased p62 degradation.

“Thus, C2C12 cells augmented the autophagic rate increasing the level of the autophagosome marker LC3, and increased p62 degradation (Ref. 92).”

• cites Ref. 92Not checked yet

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The secretion of irisin by muscle depends on AMPK signalling and, in turn, irisin has an autocrine effect, increasing the AMPK pathway and improving the metabolism and function of the muscle itself.

“All these experiments show how the secretion of irisin by the muscle depends on AMPK signalling and, in turn, irisin has an autocrine effect, increasing the AMPK pathway and thus improving the metabolism and function of the muscle itself (Fig. 3).”

Classified as probably not a substantial claim. May combine two claims.

With physical exercise and the consequent increase in irisin levels, activation of AMPK and its subsequent positive effects on energy metabolism could be promoted, resulting in a favourable process.

“With the performance of physical exercise and the consequent increase in irisin levels, the activation of AMPK and its subsequent positive effects on energy metabolism could be promoted, which results in a favourable process.”

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

Irisin could be a likely agent for anti-ageing strategies, but more research is necessary to overcome controversies regarding its use in ageing.

“In the next few decades, researchers will face the challenge of seeking anti-ageing strategies that will enable us to find healthy and disease-free ageing and irisin could be a likely agent, but more research will be necessary to overcome some controversies raised regarding the use of this promising hormone in ageing.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Meta-analyses have reported decreased irisin values in patients with coronary heart disease.

“In fact, different meta-analyses have reported decreased irisin values in patients with diseases such as coronary heart disease (Ref. 103) or osteoporosis (Ref. 104), but the reported irisin levels were highly variable, from pg to μg/ml, which limits their validity.”

• cites Ref. 103Not checked yet

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Irisin is a hormone with anti-ageing properties.

“These results determine that irisin is a hormone with anti-ageing properties, although the precise mechanism by which irisin promotes telomere lengthening is unknown.”

• cites Ref. 3Not checked yet

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May combine two claims.

Irisin is a key player during the ageing process and could be a novel target molecule for therapeutic approach to boost longevity pathways.

“In conclusion, as this revision suggests, irisin is a key player during the ageing process and it could be a novel target molecule for the therapeutic approach to boost longevity pathways.”

May combine two claims.

Part of the effects of physical exercise could be mediated by irisin signalling through activation of AMPK, SIRT1, telomere elongation and autophagy, in an autocrine and endocrine manner.

“Part of these effects could be mediated by irisin signalling, through the activation of other molecules and cellular processes associated with the promotion of healthy ageing and increased life expectancy, such as AMPK, SIRT1, telomere elongation and autophagy, both in an autocrine and endocrine manner.”

May combine two claims.

Reported irisin levels in these meta-analyses were highly variable, from pg to μg/ml, which limits their validity.

“In fact, different meta-analyses have reported decreased irisin values in patients with diseases such as coronary heart disease (Ref. 103) or osteoporosis (Ref. 104), but the reported irisin levels were highly variable, from pg to μg/ml, which limits their validity.”

• cites Ref. 103Not checked yet

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• cites Ref. 104Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Meta-analyses have reported decreased irisin values in patients with osteoporosis.

“In fact, different meta-analyses have reported decreased irisin values in patients with diseases such as coronary heart disease (Ref. 103) or osteoporosis (Ref. 104), but the reported irisin levels were highly variable, from pg to μg/ml, which limits their validity.”

• cites Ref. 104Not checked yet

  Not checked in the free run.

May combine two claims.

Scientific evidence shows irisin performs its role in various tissues such as the cardiovascular system, adipose tissue, liver, skeletal muscle, pancreas or brain, participating in metabolic processes responsible for maintaining cellular homoeostasis and stimulating anti-ageing signalling pathways, which would promote beneficial longevity with fewer diseases.

“Scientific evidence shows that irisin performs its role in various tissues such as the cardiovascular system, adipose tissue, liver, skeletal muscle, pancreas or brain, participating in metabolic processes responsible for maintaining cellular homoeostasis and stimulating anti-ageing signalling pathways, which would promote beneficial longevity with fewer diseases (Fig. 3).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Physical exercise can be recognised as a non-pharmacological strategy to counteract dysfunctions associated with age.

“Physical exercise can be recognised as a non-pharmacological strategy to counteract dysfunctions associated with age.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Other trials focus on supplementation with substances known for anti-ageing effect, such as metformin, resveratrol or vitamin D, on irisin secretion and the latter also on levels of SIRT1.

“Other trials focus on the study of supplementation with substances known for their anti-ageing effect, such as metformin (Ref. 98), resveratrol (Ref. 79) or vitamin D (Ref. 99), on irisin secretion and the latter also on levels of SIRT1.”

• cites Ref. 98Not checked yet

  Not checked in the free run.

• cites Ref. 79Not checked yet

  Not checked in the free run.

• cites Ref. 99Not checked yet

  Not checked in the free run.

May combine two claims.

There are low correlations between irisin levels measured with different ELISAs and between ELISA and mass spectrometry.

“On the other hand, the main limitation that currently exists in irisin studies is that there are low correlations between the levels of irisin measured with different enzyme-linked immunosorbent assays (ELISAs) and even rather low correlations between the values determined by ELISA and mass spectrometry (Refs 11, 101, 102), so it seems that no reliable and reproducible method is yet available for”

• cites Refs 11, 101, 102Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Natural compounds and various drugs can modulate levels of irisin and could interact with the longevity signalling pathway.

“Another interesting aspect of irisin is the potential use in preventive/therapeutic strategies, thanks to the possibility of using natural compounds and various drugs that can modulate the levels of this myokine and that could interact with the longevity signalling pathway (Table 2).”