Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4′-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.
The medical and socioeconomic advances experienced in developed countries over the last century have greatly extended life expectancy. However, health span has not increased at the same pace, resulting in the growing incidence and prevalence of age-related pathologies. Indeed, ageing remains the main risk factor for all major chronic maladies, including cardiovascular diseases, neurodegeneration and cancer1. Since the majority of ageing people are polymorbid, even considerable advances against a single age-related disease may only marginally improve health span. Therefore, tackling age-onset diseases by targeting their commonality, the ageing process itself, appears the most expedient approach. To date, only a few efficient dietary or pharmacological anti-ageing interventions exist; these include calorie restriction (the permanent reduction of total caloric intake without malnutrition) and administration of pro-longevity drugs like spermidine, rapamycin, metformin, NAD+ precursors, or resveratrol2,3. Further approaches that are able to regress (or at least delay) the onset of pathogenic age-related decline are urgently needed.
Interestingly, epidemiological studies suggest that the regular consumption of polyphenol-rich foods may decrease the risk of many chronic conditions4, and certain polyphenols—most prominently resveratrol—have been shown to extend life and/or health span in several model organisms ranging from yeast to mice5. Polyphenols are phytochemicals widely dispersed throughout the plant kingdom with manifold functions in planta ranging from pollinator attraction to pathogen and UV protection. Among them, the flavonoids represent the largest polyphenol subgroup and many of them show anti-inflammatory, anti-carcinogenic, anti-neurodegenerative and general cytoprotective properties6,7. However, reports specifically addressing the long-term effects of chemically defined flavonoids on ageing remain rare.
Most if not all behavioural, nutritional, pharmacological, and genetic manipulations that are known to extend lifespan stimulate macroautophagy (hereafter referred to as autophagy). In fact, autophagy seems to be a causal effector of these protective characteristics. For instance, the longevity drugs resveratrol, rapamycin, and spermidine, all lose their efficacy when autophagy is suppressed2. Autophagy is an intracellular recycling process, in which damaged or superfluous macromolecules and organelles are sequestered in two-membraned vesicles (autophagosomes) and then targeted to lysosomes for bulk degradation8. This facilitates the supply of recycled components for biosynthesis and thus contributes to cytoplasmic renewal and consequent cellular rejuvenation. Conversely, impairment or dysregulation of autophagic function results in age-related pathologies9,10. Altogether, autophagy is largely associated with cytoprotection and overall health.
Here we report the identification of the flavonoid 4,4′-dimethoxychalcone (DMC) as a natural autophagy inducer with phylogenetically conserved anti-ageing properties. We found that administration of DMC promotes cytoprotection and autophagy across species and that autophagy induction is required for the beneficial effects of this compound. Autophagy activation by DMC depends on specific GATA transcription factors, but not on the TORC1 kinase, a major regulatory instance of autophagy. This suggests synergistic potential with other anti-ageing interventions that do rely on TORC1 signalling.
More in the source: https://www.nature.c...467-019-08555-w
Edited by Engadin, 27 February 2019 - 03:33 PM.
