Reviewing the Ability of Calorie Restriction to Slow Aging
Calorie restriction is the most studied means to slow aging, and from this numerous lines of work have emerged, each focused on one small subset of the sweeping changes in metabolism that occur in response to a lowered intake of nutrition. Lack of nutrients puts stress on cells and organisms, and this has been the case since the emergence of life. The response to calorie restriction thus has ancient evolutionary origins, and is quite similar across all eukaryotic species investigated to date. The one big difference is that maximum life span is greatly extended in short-lived species, but not in long-lived species such as our own. Why this is the case is a matter still under investigation, and an interesting scientific puzzle, given that so many of the short-term benefits of calorie restriction are more or less the same in mice and humans.
Among the multiple alterations that have a profound impact on aging, the nutrient sensing cell pathways have recently captured much interest thanks to their potential as therapeutic targets in the prevention of age-related diseases, and the extension of the healthy life-span. The nutrient sensing pathways are mainly regrouped in the IGF (insulin-like growth factor)/insulin, the TOR (target of rapamycin), and the AMPK (AMP-Activated Protein Kinase) pathways. Data from different experimental models have largely demonstrated that the mutations that induce life-span extension are associated with an altered activity of the above-listed signaling pathways.
Interestingly, the extension of the life-span upon inhibition of the nutrient sensing signaling pathways, has also been associated to the physiological condition induced by calorie restriction (CR). Actually, CR, which consists of the reduction in the caloric intake without malnutrition, has been reported as a robust intervention to promote life-span elongation and healthy aging in rodents at the beginning of last century, and has been further suggested to have similar effects in humans. CR regimens have been shown to induce metabolic adaptations, such as reduced oxidative stress and improved inflammatory response, that ultimately result in better life- and health-spans. Studies performed on experimental models allowed to attribute the life prolongation effects to the modulation of the IGF-1, TOR, and AMPK signaling pathways, but also to other targets, such as FOXO that stimulates protein synthesis and NfkappaB, which is involved in the inflammatory response.
Nowadays, the search for the effects of long-term lifestyle interventions initiated in early adulthood and carried on throughout the entire life captures much attention, due to the evidence that in some tissues and organs, such as the skeletal muscle, the functional decline can begin in adulthood. This interest has prompted several observational studies to understand the correlation between nutrition and health-span, and the potential of CR regimens and CR mimetics in improving the health-span of aging people. At date, there is also a large number of studies aimed at directly testing CR regimens and CR-mimetics, but there are still some shadows on their efficacy, because the time and the interval of the intervention, the variability among individuals, and other factors can compromise their effectiveness.
https://www.nature.com/articles/s41591-021-01441-3
Abstract
Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.
https://onlinelibrary.wiley.com/doi/10.1111/acel.13419
Alterations in mitochondrial dynamics with age-related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility
Abstract
Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis especially mitochondrial dynamics to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24-26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4-6 months) mice hearts impair cardiomyocyte contractility and shows aging-like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to I/R stress. Furthermore, the remodeling of the mitochondria network goes together with hypoxic stress, and mitochondria undergo the processes of fusion with the increasing elongated branches during hypoxia. The transmission electron microscope data showed that cardiac SIRT1/SIRT3 deficiency in aging alters mitochondrial morphology characterized by the impairment of mitochondria fusion under I/R stress. Thus, the age-related deficiency of SIRT1/SIRT3 in the heart affects mitochondrial dynamics and respiration function that resulting in the impaired contractile function of cardiomyocytes in response to I/R.
Let's not forget the quality of life improvements from being lean and fit, some of which I won't go into ;) but I have plans to do the hike up from above the golf course to the cabin near the top on Mona Loa again, Yellowstone, and Glacier. And who knows whether a 5 year bridge will be enough to make it to the next advances (post collapse at this point).