Hacking Aging: A Strategy to Use Big Data From Medical Studies to Extend Human Life

Age is the most important single factor associated with chronic diseases and ultimately, death. The mortality rate in humans doubles approximately every eight years, as described by the Gompertz law of mortality. The incidence of specific diseases, such as cancer or stroke, also accelerates after the age of about 40 and doubles at a rate that mirrors the mortality-rate doubling time. It is therefore, entirely plausible to think that there is a single underlying process, the driving force behind the progressive reduction of the organism's health leading to the increased susceptibility to diseases and death; aging. There is, however, no fundamental law of nature requiring exponential morbidity and mortality risk trajectories. The acceleration of mortality is thus the most important characteristics of the aging process. It varies dramatically even among closely related mammalian species and hence appears to be a tunable phenotype. Here, we follow how big data from large human medical studies, and analytical approaches borrowed from physics of complex dynamic systems can help to reverse engineer the underlying biology behind Gompertz mortality law. With such an approach we hope to generate predictive models of aging for systematic discovery of biomarkers of aging followed by identification of novel therapeutic targets for future anti-aging interventions

Identification of 12 genetic loci associated with human healthspan

Aleksandr Zenin et al. present a genome-wide association study and genetic risk model for human healthspan, the length of morbidity-free life. They identify 12 loci associated with healthspan and osbserve genetic correlations between healthspan and life-history and lifestyle traits, such as obesity and smoking

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases.This work was funded by the European Regional Development Fund, European Union’s Horizon 2020 Research and Innovation Programme (BATCure grant No. 666918 to J.P.B., S.E.M., D.L.M., S.S., and T.R.M.; PANA grant No. 686009 to A.A.), Agencia Estatal de Investigación (PID2019-105699RB-I00/AEI/10.13039/501100011033 and RED2018‐102576‐T to J.P.B.; SAF2017-90794-REDT to A.A.), Instituto de Salud Carlos III (CB16/10/00282 to J.P.B.; PI18/00285; RD16/0019/0018 to A.A.), Junta de Castilla y León (CS/151P20 and Escalera de Excelencia CLU-2017-03 to J.P.B. and A.A.), Ayudas Equipos Investigación Biomedicina 2017 Fundación BBVA (to J.P.B.), and Fundación Ramón Areces (to J.P.B. and A.A.). SM benefits from MRC funding to the MRC Laboratory for Molecular Cell Biology University Unit at UCL (award code MC_U12266B) towards lab and office space. Part of this work was funded by Gero Discovery L.L.C. M.G.M. is an ISCIII-Sara Borrel contract recipient (CD18/00203)

Aberrant upregulation of glycolysis mediates CLN7 neuronal ceroid lipofuscinosis

Resumen del trabajo presentado en el 43rd Annual Meeting of the Spanish Society of Biochemistry & Molecular Biology, celebrado en Barcelona, del 19 al 22 de julio de 2021CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in the autophagy-lysosomal pathway causes accumulation of structurally and bioenergetically impaired neuronal mi- tochondria. In vivo genetic approach revealed elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolysis activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFK- FB3, a glycolytic-promoting enzyme normally unstable in healthy neurons. Pharmacological inhibition of PFKFB3 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectified key disease hallmarks. Thus, aberrant upregulation of neuronal glycolysis contributes to CLN7 patho-genesis and targeting PFKFB3 may alleviate this and other lysosomal storage diseasesThis work was funded by Agencia Estatal de Investigación (PID2019-105699RB-I00).Peer reviewe

Structure-based drug design of a new chemical class of small molecules active against influenza A nucleoprotein in vitro and in vivo

We report preliminary results and a summary of a bottom-up approach to identify new, active, nontoxic, small-molecule antivirals designed to have а novel mechanism of action. We employed the procedure to identify 3-mercapto-1,2,4-triazoles derivatives as potential NP inhibitors in silico and subsequently demonstrated the in vitro efficacy of the molecules against various strains of the influenza A virus. The most efficacious compounds were successfully tested in an in vivo influenza challenge experiment