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Translating the biology of aging into novel therapeutics for Alzheimer disease.

ABSTRACT: Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer disease (AD), a progressive neurodegenerative disease with currently no therapies that prevent, slow, or halt disease progression. Like other chronic diseases of old age, the progressive pathology of AD begins decades before the onset of symptoms. Many decades of research in biological gerontology have revealed common processes that are relevant to understanding why the aging brain is vulnerable to AD. In this review, we frame the development of novel therapeutics for AD in the context of biological gerontology. The many therapies currently in development based on biological gerontology principles provide promise for the development of a new generation of therapeutics to prevent and treat AD.

SUBMITTER: Hara Y

PROVIDER: S-EPMC6340342 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Translating the biology of aging into novel therapeutics for Alzheimer disease.

Hara Yuko Y McKeehan Nicholas N Fillit Howard M HM

Neurology 20181207 2

Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer disease (AD), a progressive neurodegenerative disease with currently no therapies that prevent, slow, or halt disease progression. Like other chronic diseases of old age, the progressive pathology of AD begins decades before the onset of symptoms. Many decades of research in biological gerontology have revealed common processes that are relevant to understanding why the aging brain is vulnerable to AD. In ...[more]

PMID: 30530798

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Project description:BACKGROUND:Although telomerase has potential for age-related disease intervention, the overexpression of telomerase in about 90% of cancers, and in HIV virus reservoirs, cautions against se in anti-aging telomerase therapeutics. While multiple reviews document the canonical function of telomerase for maintenance of telomeres, as well as an increasing numbers of reviews that reveal new non-canonical functions of telomerase, there was no systematic review that focuses on the array of associates of the subunit of Telomerase Reverse transcriptase protein (TERT) as pieces of the puzzle to assemble a picture of the how specific TERT complexes uniquely impact aging and age-related diseases and more can be expected. METHODS:A structured search of bibliographic data on TERT complexes was undertaken using databases from the National Center for Biotechnology Information Pubmed with extensive access to biomedical and genomic information in order to obtain a unique documented and cited overview of TERT complexes that may uniquely impact aging and age-related diseases. RESULTS:The TERT associations include proper folding, intracellular TERT transport, metabolism, mitochondrial ROS (Reactive Oxygen Species) regulation, inflammation, cell division, cell death, and gene expression, in addition to the well-known telomere maintenance. While increase of cell cycle inhibitors promote aging, in cancer, the cell cycle check-point regulators are ambushed in favor of cell proliferation, while cytoplasmic TERT protects a cell cycle inhibitor in oxidative stress. The oncogene cMyc regulates gene expression for overexpression of TERT, and reduction of cell cycle inhibitors-the perfect storm for cancer promotion. TERT binds with the oncogene RMRP RNA, and TERT-RMRP function can regulate levels of that oncogene RNA, and TERT in a TBN complex can regulate heterochromatin. Telomerase benefit and novel function in neurology and cardiology studies open new anti- aging hope. GV1001, a 16 amino acid peptide of TERT that associates with Heat Shock Proteins (HSP's), bypasses the cell membrane with remarkable anti disease potential. CONCLUSIONS:TERT "associates" are anti-cancer targets for downregulation, but upregulation in antiaging therapy. The overview revealed that unique TERT associations that impact all seven pillars of aging identified by the Trans-NIH Geroscience Initiative that influence aging and urge research for appropriate targeted telomerase supplements/ stimulation, and inclusion in National Institute on Aging Intervention Testing Program. The preference for use of available "smart drugs", targeted to only cancer, not off-target anti- aging telomerase is implied by the multiplicity of TERT associates functions.

Project description:Background"Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.MethodsWe modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education.ResultsAdvanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.ConclusionsWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

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Translating the biology of aging into novel therapeutics for Alzheimer disease.

Publications

Translating the biology of aging into novel therapeutics for Alzheimer disease.

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