The epigenetics of frailty.

The conceptual change of frailty, from a physical to a biopsychosocial phenotype, expanded the field of frailty, including social and behavioral domains with critical interaction between different frailty models. Environmental exposures - including physical exercise, psychosocial factors and diet - may play a role in the frailty pathophysiology. Complex underlying mechanisms involve the progressive interactions of genetics with epigenetics and of multimorbidity with environmental factors. Here we review the literature on possible mechanisms explaining the association between epigenetic hallmarks (i.e., global DNA methylation, DNA methylation age acceleration and microRNAs) and frailty, considered as biomarkers of aging. Frailty could be considered the result of environmental epigenetic factors on biological aging, caused by conflicting DNA methylation age and chronological age.

The present narrative review describes the available evidence about epigenetic biological markers of frailty considered aging biomarkers, among others. Aging biomarkers can help in identifying frail and older individuals affected by multiple diseases to further increase the power of composite biomarker panels in the diagnostic and prognostic process. Among combined biomarkers, epigenetic regulators with different methylation patterns and small molecules such as microRNAs are included. Given that frailty involves multiple biological systems, it is possible to define it according to a novel model, including emotional and social domains and the influence of environmental factors, named the biopsychosocial phenotype. Different epigenetic biomarkers of frailty, from the first generation to the more specific and recent second-generation epigenetic aging biomarkers, may account for factors linked to different cellular types, such as heterogeneity, and a reverse causation process that requires integration with gene expression. A better understanding of the relationships among frailty, multimorbidity and overall mortality will help us to identify the best therapeutic targets.

Lessons learned from the failure of solanezumab as a prospective treatment strategy for Alzheimer's disease.

INTRODUCTION: In the last decade, the efforts conducted for discovering Alzheimer's Disease (AD) treatments targeting the best-known pathogenic factors [amyloid-ß (Aß), tau protein, and neuroinflammation] were mostly unsuccessful. Given that a systemic failure of Aß clearance was supposed to primarily contribute to AD development and progression, disease-modifying therapies with anti-Aß monoclonal antibodies (e.g. solanezumab, bapineuzumab, gantenerumab, aducanumab, lecanemab and donanemab) are ongoing in randomized clinical trials (RCTs) with contrasting results. AREAS COVERED: The present Drug Discovery Case History analyzes the failures of RCTs of solanezumab on AD. Furthermore, the authors review the pharmacokinetics, pharmacodynamics, and tolerability effect of solanezumab from preclinical studies with its analogous m266 in mice. Finally, they describe the RCTs with cognitive, cerebrospinal fluid and neuroimaging findings in mild-to-moderate AD (EXPEDITION studies) and in secondary prevention studies (A4 and DIAN-TU). EXPERT OPINION: Solanezumab was one of the first anti-Aß monoclonal antibodies to be tested in preclinical and clinical AD showing to reduce brain Aß level by acting on soluble monomeric form of Aß peptide without significant results on deposits. Unfortunately, this compound showed to accelerate cognitive decline in both asymptomatic and symptomatic trial participants, and this failure of solanezumab further questioned the Aß cascade hypothesis of AD.

The Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Carriers of one copy of the apolipoprotein E gene (APOE) ε4 allele have a 4-fold increased AD risk, while APOE ε4/ε4-carriers have a 12-fold increased risk of developing AD in comparison with the APOE ε3-carriers. The main longevity factor is the homozygous APOE ε3/ε3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene may affect tau- and amyloid-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significantly associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotide sites of APOE.