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Principal Investigator: GARY B RUVKUN
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2021
Award: $344,400
Funding agency: National Institute on Aging
Project Summary/Abstract:
C. elegans surveils the mitochondrion for deficits and couples to an endocrine system of detoxification,
innate immunity, and longevity control. This coupling of immunity and detoxification pathways to lifespan
regulation has been observed in mice as well. Our analysis of immune responses triggered by
mitochondrial dysfunction in C. elegans has revealed that the RNA interference antiviral axis is strongly
induced by a variety of mitochondrial defects. The mitochondrial MAVS to RNA helicase system is highly
integrated into mammalian NF-kB antiviral cascades; we discovered that in C. elegans mitochondrial
dysfunction is coupled to the RNAi antiviral system used by most fungi and plants, and some animals
such as C. elegans. Our discovery that protein N-glycosylation by PNG-1/NGLY1 mediates the
deamidation of N-glycosylated asparagine residues from ER-localized proteins to aspartic acid has
important implications for viral immunity. Many viral proteins are N-glycoyslated, including 22 such
modifications on the Covid Spike protein, and our informatic analysis shows a strong signature of
NGLY1-mediated protein editing for some Spike protein N-glycosylations. Viral immunity emerged in this
past year as one of the major differences between the elderly and young adults: the death rate from
Covid is 10x higher than the relative increase in death rate from any cause in over 65 year old adults
compared to young adults. Thus a study of the molecular basis of viral immunity intersects the biology of
aging. Our genetic analysis of how C. elegans surveils its mitochondria and other core cellular
components for attacks to activate longevity programs as well as to innate immune and detoxification
responses is a very non-standard view of innate immunity and aging. But the intersection with for
example the use of rapamycin as an anti-aging drug is profound. We continue to focus on C. elegans in
this proposal. Over the past five years, C. elegans classical genetic analysis, screening for mutant
phenotypes and deducing the molecular defect that causes the phenotype by genome sequencing, has
been transformed by low cost full genome sequencing of newly isolated mutants. All of the genes we
propose to study have strong orthologues in humans, and are likely to function in humans in an ancient
conserved pathway for detection of microbial assaults and control of the aging process by such
surveillance. Variation in these same pathways will reveal how humans respond appropriately and
inappropriately to drugs or bacterial pathogens, or activate drug detoxification pathways in the absence
of a trigger. Such variation may also be the cause of diseases as diverse as anorexia nervosa, migraine,
and autoimmunity, which, along with lifespan itself, are highly gender biased. Our proposal to study how
the microbial flora attempt to subvert these pathways will also reveal how variation in the microbiome
may underlie variation in human longevity.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><21+ years old><65+ years old><AD dementia><AD model><ATP-protein phosphotransferase><Abscission><Adult><Adult Human><Aged 65 and Over><Aging><Alleles><Allelomorphs><Alzheimer><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease dementia><Alzheimer's disease model><Alzheimers Dementia><Alzheimers disease><Amino Acid Sequence><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Animals><Anorexia Nervosa><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antivirals><Asparagine><Aspartic Acid><Autoimmune Status><Autoimmunity><Autoregulation><Aβ><Binding Site Domain><Biology of Aging><Body Tissues><C elegans><C. elegans><C.elegans><COVID><COVID-19><COVID19><CV-19><CV19><Caenorhabditis><Caenorhabditis elegans><Cats><Cats Mammals><Chromosomal Synapsis><Chromosome Mapping><Chromosome Pairing><Client><CoV disease><Complex><Coupled><Couples><Coupling><DA Neuron><DNA><DNA Binding Domain><DNA Recombination><DNA-Binding Protein Motifs><Dam methyltransferase><Death Rate><Defect><Deoxyribonucleic Acid><Detection><Dexamethasone><Diagnostic><Dioxygenases><Disease><Disorder><Domestic Cats><Dopamine><Dopamine neuron><Dreams><Drug Metabolic Detoxication><Drug Metabolic Detoxification><Drugs><E coli><E. coli><Elderly><Elements><Endocrine system><Endocrine/Metabolic Organ System><Escherichia coli><Esteroproteases><Excision><Extirpation><Feline Species><Felis catus><Felis domestica><Felis domesticus><Felis sylvestris catus><Fruit><Gases><Gender Bias><Gene Amplification><Gene Copy Number><Gene Dosage><Gene Expression><Gene Localization><Gene Mapping><Gene Mapping Genetics><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Recombination><Genetic Screening><Genetic analyses><Genetic defect><Genomic Segment><Homeostasis><Hormonal System><Human><Hydroxytyramine><Immune><Immune response><Immunes><Immunity><Immunoglobulin Enhancer-Binding Protein><Immunological response><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Informatics><Injections><Innate Immunity><Intestinal><Intestines><Kinase Family Gene><L-Asparagine><L-Aspartic Acid><Late-Onset Disorder><Length of Life><Libraries><Ligand Binding Domain><Linkage Mapping><Longevity><Macropain><Macroxyproteinase><Maps><Mediating><Medication><Messenger RNA><Metabolic Drug Detoxications><Metabolic Glycosylation><Metabolic/Endocrine Body System><Metabolism of Toxic Agents><Methylation><Methyltransferase Gene><Mice><Mice Mammals><Migraine><Migraine Headache><Mitochondria><Modern Man><Modification><Molecular><Monitor><Multicatalytic Proteinase><Murine><Mus><Muscle><Muscle Tissue><Mutation><NF-kB><NF-kappa B><NF-kappaB><NFKB><Native Immunity><Natural Immunity><Nematoda><Nematodes><Nerve Transmitter Substances><Neurotransmitters><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Nuclear Factor kappa B><Nuclear Hormone Receptor Superfamily><Nuclear Hormone Receptors><Nuclear Transcription Factor NF-kB><O element><O2 element><Operon><Oxygen><PINK1><PINK1 gene><Palsy><Paralysed><Paralysis Agitans><Parkinson><Parkinson Disease><Parkinson's disease><Parkinsons disease><Partial Pressure><Pathway interactions><Patients><Pedigree><Peptidases><Peptide Hydrolases><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Phylogenetic Analysis><Phylogenetics><Physiological Homeostasis><Plants><Plegia><Polyploid><Polyploidy><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Primary Parkinsonism><Primary Protein Structure><Primary Senile Degenerative Dementia><Process><Production><Prosome><Protease Gene><Proteases><Proteasome><Proteasome Endopeptidase Complex><Protein Kinase><Proteinases><Proteins><Proteolytic Enzymes><Proteosome><Quelling><Quinone Compound><Quinones><RNA><RNA Gene Products><RNA Helicase><RNA Interference><RNA Seq><RNA Silencing><RNA interference screen><RNA sequencing><RNAi><RNAi screen><RNAi-based screen><RNAseq><Rapamune><Rapamycin><Receptor Gene><Recombination><Regulation><Removal><Resistance><Ribonucleic Acid><Running><Sequence-Specific Posttranscriptional Gene Silencing><Sex Bias><Sexism><Short interfering RNA><Sirolimus><Small Interfering RNA><Small RNA><Surgical Removal><Synapsis><System><Testing><Tissues><Total Human and Non-Human Gene Mapping><Transcription Factor NF-kB><Variant><Variation><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral N Protein><Viral Proteins><Virus><Virus Diseases><a beta peptide><abeta><adult youth><adulthood><advanced age><age 65 and greater><age 65 and older><aged 65 and greater><aged ≥65><alzheimer model><amyloid beta><amyloid-b protein><anti aging><anti aging drug><anti aging medicine><anti-viral agents><anti-viral drugs><anti-virals><antiaging><antiaging drug><antiaging medicine><assault><bacteria pathogen><bacterial pathogen><beta amyloid fibril><bowel><corona virus disease><corona virus disease 2019><coronavirus disease><coronavirus disease 2019><cost><dam methylase><deamidation><dementia of the Alzheimer type><detoxification><dietary fruit><dopaminergic neuron><dreaming><drug/agent><elders><endocrine gland/system><entire genome><full genome><fungus><fusion gene><gain of function><genetic analysis><genetic mapping><genetic pedigree><genome editing><genome mutation><genome sequencing><genomic editing><genomic region><geriatric><glycogen synthase a kinase><glycosylation><host response><human old age (65+)><hydroxyalkyl protein kinase><immune system response><immunoresponse><kappa B Enhancer Binding Protein><late disease onset><late life><late onset disorder><later life><life span><lifespan><mRNA><mRNA capping><microbial><microbial consortia><microbial flora><microbiome><microbiota><microflora><mitochondrial><mitochondrial dysfunction><mitochondrial genome><mitochondrial membrane><multicatalytic endopeptidase complex><multispecies consortia><muscular><mutant><mutation scanning><mutation screening><natural gene amplification><nuclear factor kappa beta><old age><older adult><older person><paralysis><paralytic><pathogenic bacteria><pathway><pedigree structure><phosphorylase b kinase kinase><primary degenerative dementia><programs><protein kinase BRPK gene><protein sequence><resection><resistant><response><restriction enzyme><roundworm><screening><senile dementia of the Alzheimer type><senior citizen><siRNA><soluble amyloid precursor protein><sugar><transcriptome sequencing><viral infection><virus infection><virus protein><virus-induced disease><whole genome><young adult><young adulthood>