DEVELOPMENT OF NUTRACEUTICAL INGREDIENTS (PLANT EXTRACTS) TO SLOW DOWN THE BIOLOGICAL AGING

Background: Accelerating population aging is a global challenge, straining healthcare system and workforce while requiring solutions to extend healthspan and slow biological aging. Telomere shortening, aberrant DNA methylation, oxidative stress and inflammation, play a pivotal role in cellular aging and chronic disease development. Natural extracts, including polyphenols, offer promising anti-aging benefits by modulating oxidative damage and inflammation. Additionally, natural dietary molecules and extracts influence epigenetic mechanisms by inhibiting DNA methyltransferase (DNMT). Further, conducting studies on different age-related conditions and exploring strategies to mitigate biological aging offer novel approaches to promote healthy aging. Aims: Supported by the PON Research and Innovation 2014-2020 programme on Green Topics, this research aimed to develop nutraceutical strategies for healthy aging, focusing on new extracts and formulations, including Monarda didyma L. extract, epigenetic effects of natural dietary molecules and extracts, particularly on DNMT inhibition, and alternative strategies to mitigate biological aging. Main findings: 1) Monarda didyma L. extract effects were investigated on biological aging markers both in vitro studies and in a randomized, placebo-controlled, double-blind clinical trial (NCT05399966) conducted at the Occupational Medicine Unit-AOUP in n=81 aging workers (45-65 years). In vitro analyses revealed antioxidant activity, reduced telomere shortening and cellular senescence, protected against DNA damage and improved endothelial function (p<0.05). Clinical trial demonstrated that 12-week extract supplementation improved leukocyte telomere length (p=0.05) and stabilized DNA methylation age (DNAmAge) and mitochondrial DNA copy number in the intervention group (G1), while the placebo group (G2) showed accelerated DNAmAge (p<0.0001) and hypermethylation of age-related genes (ELOVL2, FHL2) (p=0.045). G1 also reported a maintenance of a better hematological condition (p<0.05), enhanced quality of life (p=0.008) particularly in the physical domain (p=0.035), better movement and sleep indices (p≤0.05) detected by questionnaires and Miband7 devices, highlighting the extract’s potential as a natural anti-aging candidate. 2) During my study period at Swiss Mibelle Biochemistry company, extracts with anti-aging and antioxidant effects were developed, focusing on optimization of extraction processes, evaluation of flavonoid compounds through HPLC, development of new formulations (lozenges), stabilization and conservation tests of products. Each step ensures the efficacy, safety and stability of innovative natural anti-aging products. 3) A systematic review (n=68 studies) identified natural dietary molecules and extracts that directly influence DNA methylation and their minimum effective dose. In vitro (n=59; 86.8%), in vivo (n=2; 2.9%), ex vivo (n=2; 2.9%) and combined (n=5; 7.3%) studies demonstrated that molecules such as epigallocatechin gallate, quercetin, sulforaphane, curcumin, genistein, resveratrol, apigenin and gallic acid inhibit DNMT, reducing methylation in specific DNA regions and activating specific genes with inhibitory effects on cancer development. The interplay between these molecules, also known for their anti-inflammatory and antioxidant properties, and DNMT, considering the minimum effective dose, represents a promising area for epigenetic aging modulation and cancer prevention. 4) Additional studies aimed at explored strategies to mitigate biological aging, examining the biological aging of pauci- and asymptomatic healthcare workers (n=76) infected during COVID-19 pandemic, addressing aging-related challenges associated with spaceflight in a review (n=66 studies), and evaluating the effectiveness of visual arts-mediated Cognitive Activation Therapy as a non-pharmacological intervention in patients with neurocognitive disorders (n=20).