The malin gene encodes a RING type E3-ubiquitin ligase which forms a functional complex with laforin, a glucan phosphatase . Mutations in either malin or laforin in humans lead to the development of Lafora progressive myoclonus epilepsy, a rare fatal neurodegenerative disease with early manifestations in the early childhood. Brain damage is incurred due to deposition underbranched and hyperphosphorylated insoluble glycogen in the brain and peripheral tissues [20,21,22]. It is notable that glucan deposits have been described in the setting of aging animals and humans [23,24,25], unrelated to Lafora disease, which raises the possibility of lesser malin activity with age. Indeed, malin appears to participate in a delicate homeostatic network linking neuronal glycogen synthesis and energetic utilization, interacting with autophagy, mitochondrial function, and response to thermal stress, which could collectively affect lifespan [19, 25,26,27,28]. The possibility that malin expression, which is critical for inhibition of polyglucan deposits in neurons, plays a role in healthful longevity in humans is intriguing and requires targeted research. In animal studies malin deficiency can lead to impaired autophagy and accumulation of dysfunctional mitochondria, which eventually promote neurodegeneration, immune disorders, cancer, and accelerated aging .
Secretagogin is an intracellular calcium sensor and facilitator of insulin secretion by pancreatic islet beta cells . Recently it was shown that secretagogin plays a critical role in the second phase of glucose-stimulated insulin secretion , protects against insulin aggregation, and enhances peripheral response to insulin . Concordant with this broad role in carbohydrate handling, secretagogin knockout leads to hyperglycemia . Secretagogin is also expressed in neuroendocrine cells where it likely regulates exocytosis and hormone release [33, 34]. Concordantly, it is also involved in danger avoidance behavior through the control of post synaptic cell surface availability of NMDA receptors in the central amygdala . We are not aware, however, of published reports examining the relation between induced changes in secretagogin expression and lifespan or longevity.
Of major interest in the Horvath algorithm are CpG sites with a negative contribution to the epigenetic age, such as frataxin. Frataxin is a nuclear-encoded mitochondrial protein which is part of the Fe-S-cluster-containing proteins acting as an iron chaperone, thereby allowing normal function of the mitochondrial respiratory chain . In our analysis frataxin shows both high inter-personal variability and also partly explains some (~ 8%) of the calculated age difference between epigenetically old and average subjects (Fig. 3A). The fact that higher methylation of frataxin can extend life, as indirectly suggested by its epigenetic age lowering effect is somewhat counterintuitive: defects in the expression of this mitochondrial protein cause the neurodegenerative syndrome of Friedreich’s ataxia [37, 38], which is also accompanied by cardiomyopathy, diabetes mellitus, and reduced life expectancy . However, inactivation of many mitochondrial genes in the nematode Caenorhabditis elegans by RNAi was actually shown to extend lifespan . Ventura et al. reported that suppression of the frataxin homolog gene (frh-1) prolonged lifespan in the nematode, along with an altered phenotype of smaller size, diminished fertility, and variant responses to oxidative stress. Thus, whereas sizable inactivation of frataxin causes a disabling disease, a more moderate frataxin suppression, such as achieved by RNAi, could lead to higher lifespan as seen in C. elegans . There is evidence that frataxin silencing induces mitochondrial autophagy as an evolutionarily conserved response to the ensuing iron starvation . In a broader sense, lesser frataxin availability might comprise a surmountable challenge which elicits mitophagy that eventually preconditions the cell’s capacity to sustain future stress, thereby increasing the likelihood of extended lifespan.
Our findings of inter-personal variabilities in the epigenetic age components of the healthy population have raised our interest in discovering epigenetic age patterns of individuals with biological age accelerating diseases, such as diabetic patients. Our results did not reflect epigenetic age acceleration for T2D and showed rather the opposite, for T1D subjects which had lower epigenetic age than the average of the healthy population (under the red curve in Fig. 5). Nevertheless, these results are in agreement with earlier publications which have also used chronological age-based epigenetic age calculators, such as Horvath’s epigenetic clock [8, 42]. This may indicate that the CpG probes chosen for the construction of such epigenetic age clocks do not reflect variations in DNA methylation leading to epigenetic age drifting in diabetes or its complications. What makes the T1D population “epigenetically younger” according to the aging clock used in this study would be an interesting question for future investigations. Notably, a different epigenetic clock type, the “DNAm GrimAge,” which incorporates DNA methylation sites related to surrogate biomarkers of smoking level and of selected plasma proteins, that are strongly associated with mortality and morbidity, may be a better choice for predicting age acceleration in diabetics [3, 4, 42].
Of the top five most variable age components that are found solely in the diabetic cohort, PAWR is a tumor suppressor gene, inducing selective apoptosis of cancer cells [43,44,45], and may thus be related to association of aging with higher cancer rates. Another components is related to PIPOX which catalyze the oxidation of L-pipecolate, an intermediate step in the catabolic process of L-lysine to acetyl-CoA, produced in the pipecolate pathway [46, 47]. Elevated levels of lysine were found to be associated with higher risk for the development of T2D and for T2D-concomitant cardiovascular disease (CVD) . In addition, PIPOX promotes sarcosine oxidative N-demethylation, yielding glycine , as part of the sarcosine pathway, which is involved in the methionine cycle [50,51,52,53]. The methionine cycle is responsible for the production of S-adenosylmethionine (SAM), the methyl donor substrate in the process of cytosine DNA methylation by the family of DNA methyl transferase (DNMT) enzymes. Differential levels of PIPOX and sarcosine were observed in several types of cancers [49, 54]. In addition, methionine cycle restriction and regulation of SAM production were shown to extend lifespan in various animal models .