Select Two Nodes

• ▼ [200] Extracellular Spaces: ECM, Blood Plasma, Lymph, CSF
  • [201] Level of IL-15 and IL-15Ra in serum
  • [202] Glucose Concentration in Bloodstream. (Moderate in healthy people; higher in Diabetes)
  • [203] Glycation: sugars bond to extracellular proteins
  • [204] Glycated extracellular proteins form AGEs and crosslinks
  • [205] Igs crosslink to kidney glomerular Basement Membrane, causing complement-mediated damage
  • [206] Glycated Arginine can convert to Ornithine
  • [207] Altered Arg and Asp residues disrupt RGD cell attachment
  • [208] ECM protein residues can deamidate or isomerize, which might change folding
  • [209] Extracellular ROS
  • [210] ROS and sugars peroxidize lipids and glycate proteins in circulating LDL
  • [211] A-beta oxidizes cholesterol and fatty acids, generates H2O2 and OH* radicals
  • [212] Antioxidants in EC fluids quench ROS
  • [213] A-beta monomers aggregate with Zn, Cu, to form toxic A-beta oligos and plaques
  • [214] metal ionophores disaggregate toxic A-beta oligos. take Cu, Zn and release A-beta monomer.
  • [215] Cu, Zn and A-beta monomer released into glutamatergic synapses during neurotransmission
  • [216] EC Zn
  • [217] Metal Ionophores take Cu, Zn into neuron
  • [218] A-beta monomer slowly cleared by glymphatic transport to lymph and urine
  • [219] MMP2 and 3 slowly digest A-beta monomer
  • [220] Zn/Cu activate MMP2and3
  • [221] Glycated LDL and RBCs crosslink to endothelial arterial collagen
  • [222] Ca ++ and Lipids bound to elastin
  • [223] Oxidation and cleavage of ECM proteins
  • [224] Damaged, crosslinked, glycated, oxidized ECM proteins accumulate and change EC environment
  • [225] Elastic fibers
  • [226] TTR-amyloid in muscle and elsewhere
  • [227] Cerebral amyloid angiopathy decreases endothelial health
  • [228] Good Hormone Levels
  • [229] Beta-2-microglobulin, and Chemokines, incl CCL11, in plasma and CSF
  • [230] EGF, FGF
  • [231] TGF-beta levels in satellite cell niche, B marrow, and blood
  • [235] Articlular cartilage deteriorates
  • [236] GnRH in Hypothalamus maintains youth
  • [238] Interstitial spaces in brain increase during sleep. Gamma brainwave entrainment activates microglia, enhancing clearance of A-beta
  • [239] FGF2 and VEGF secreted by astrocytes, microglia, NSCs, and NPCs.
  • [240] Osteocalcin in blood
  • [241] Wnt signaling proteins in serum
  • [242] Racemization of L- to D-Asp with aging of long-lived protein cause A-beta and alpha-synuclein fibrils
  • [243] Transferrin carries Iron in blood plasma
  • [244] Bone deposition in cribiform plate restricts clearance of CSF and A-beta
  • ▼ [800] Secretion into Extracellular Spaces
    • [232] MMPs secreted by arrested cells
    • [234] Hypochlorous acid secreted by inflammatory macrophages

• ▼ [801] Cytosolic Compartment of the Cell
  • [013] Spermidine is anti-ox, anti-inflamm, enhances autophagy, improves anti-cancer immunity, and decreases histone H3 acetylation
  • [014] Lipofuscin in cytoplasm can trigger Apoptosis
  • [015] H2O2 in cytoplasm
  • [017] REST protein levels in neurons.
  • [018] Sprouty-1 needed for satellite prolif
  • [048] Levels of miRNA in brain change
  • [063] Catalase and cytosolic GPx degrade H2O2.
  • [064] Redox Potential poise in cytoplasm increased by oxidation. This changes intracellular signaling and gene expression
  • [065] Damaged Junk to be repaired or disassembled
  • [066] Glycation: sugars, AGEs, and ALEs bond to intracellular proteins
  • [067] Damaged proteasome subunits turn- over by CMA
  • [068] Junk molecules aggregate and crosslink if not quickly disassembled
  • [069] Hyperphosphorylated Tau forms PHF, which bind Cu, produce H2O2
  • [070] Proteasomes digest damaged cytoplasmic proteins
  • [071] Cytoplasmic ROS attack intracellular and membrane proteins and lipids. Enzymes and proteasomes get inactivated
  • [072] Tau hyper- phosphorylation destabilizes microtubules, blocks axon transport.
  • [073] Reactive Aggregates, giant mitochondria, and LF-filled Lysosomes accumulate in cytoplasm, generate ROS, and impair cell functioning
  • [074] Aggs block and inhibit Proteasomes
  • [075] Oxidized pigment enzymes in hair follicles turn hair white
  • [080] Cytoplasmic antioxidants quench ROS
  • [081] Endogenous Antioxidant Production
  • [083] Intracellular Ca2+ levels rise and generate ROS
  • [084] Intraneuronal Fe generates ROS
  • [086] Low Zn makes neurons sick
  • [087] Excitotoxicity kills neurons
  • [088] Zn supply in neurons
  • [090] MAPK pERK signaling
  • [092] cAMP level in cytoplasm of PFC neurons
  • [739] Induce Exocytosis of LF - filled Lysosomes
  • ▼ [802] Cell Membrane
    • [016] CD38 degrades NAD+
    • [076] Oxidized membrane lipids and proteins degrade transporters of Ca2+, Na+, Glu, and glucose; promote depolarization and Ca2+ influx
    • [077] Reductive Hotspot: Anaerobic cells and muscle fiber segments export electrons through plasma membrane, generating extracellular ROS
    • [078] Peroxidized Lipids and oxidized cholesterol in LDL are imported by other cells, and incorporated into membranes, damaging membranes and mitosis via lipid chain-reactions
    • [079] Normal A-beta in membrane reacts with Cu, producing H2O2 and ROS
    • [082] RAGE and Scavenger Receptors
    • [085] Fe exported from neuron to EC transferrin
    • [089] Notch receptor
    • [091] Delta Ligand
    • [093] cAMP opens K+ channels, stops PFCNs from firing
    • [095] ZnT3 pumps Zn and Cu into neurons
    • [096] alpha-2A receptors in PFCN membranes
    • [163] GnRH secretion from Hypothalamus
  • ▼ [803] Lysosome - Hydrolysis - for recycling. Accumulation in nonmitotic cells
    • [001] Lysosomes digest Junk, until they become filled with LF
    • [002] ROS oxidize proteins and lipids
    • [003] Free Fe, released by digestion, or trapped in LF, reacts with H2O2 to make HO*
    • [004] LF - filled Lysosoms have reduced capacity and reduced rate of digesting Junk. They demand more lytic enzymes from Golgi, so less enzymes go to functional Lysosomes. Apgy becomes inhibited when Lysms cannot accept more junk.
    • [006] Oxidized lipids, proteins, and Fe crosslink to form Lipofuscin
    • [008] Lipofuscin accumulates in Lysosomes of Post-Mitotic cells
    • ▼ [804] Lysosome Membrane
      • [005] Lamp2a imports tagged soluble cytoplasmic proteins to digest.
      • [007] LF - filled Lysosomes with damaged membranes spill lytic enzymes and reactive LF into cytoplasm
      • [009] ROS in Lysosomes cause damage to Lysosomal membranes or membrane scaffolding which controls vesicle fusions
      • [010] H2O2 diffuses into Lysm
  • ▼ [805] Macroautophagy
    • [011] Autophagosome detect damaged Lysosomes, engulf them, transport to new Lysosome for digestion.
    • [012] Autophagosomes engulf junk, old mitos, organelles, proteasomes, ribosomes, damaged membranes and nuclear scaffolding. Transport to Lysosome for digestion.
    • [033] Vitamin C, Spermidine, Fasting enhance rate of autophagy.
  • ▼ [806] Mitochondria in nonmitotic cell
    • [404] Cardiolipin bends IMM, enhancing ETC function
    • [417] Giant mitochondria accumulate when damage impairs mitochondria fission. They can?t be autophagized, and they produce more ROS.
    • [418] ROS generated by mitochondrial metabolism
    • [419] Mitochondrial Antioxidants quench some ROS
    • [420] Damaged mitos produce less ATP and more ROS; have lower memb pot. Most are autophagized to Lysosome.
    • [421] mt ROS attack IMM, cardiolipin, mt proteins, and mtDNA
    • [422] Damaged mtDNA or replication machinery
    • [423] mtDNA replication mistakes generate insertions, deletions
    • [424] O2* - converted to H2O2 by SOD
    • [425] Lon Protease digests damaged mt proteins
    • [426] Lon Protease Levels decline with age
    • [427] Fe-S Cluster assy depends on mt memb potential
    • [428] mutant mtDNA
    • [429] mt GPx degrades H2O2
    • [430] Functionality of collective mt population
    • [431] Rate of mito biogenesis
    • [432] Clonal amplification of mutant mtDNA causes PM cell or skeletal muscle fiber segment to become anaerobic
    • ▼ [807] Mitochondria Membrane
      • [416] H2O2 diffuses out of mitochondria
  • ▼ [808] Cell Nucleus - Genetics
    • [302] pre-Lamin-A accumulates
    • [332] GnRH gene expn in hypothalamus
    • [333] Epigenetic Methylation of DNA
    • [334] Acetylation of Histones
    • [335] PGC-1-alpha PGC-1-beta
    • [336] Lon Protease mRNA
    • [337] Chromatin conformation is altered
    • [338] Telomeres oxidized, damaged, or made too short
    • [339] p53 rises
    • [340] DNA repair PARP-1 activated
    • [341] Nuclear 20S proteasome removes damaged proteins
    • [342] Genome integrity proteins contain Fe-S Clusters.
    • [343] Position Effect of genes near short Telomeres alters expression
    • [344] Developmental Differentiation reduces Telomerase expression
    • [345] Short Tmeres => end-joining chromosomes => nondysjunction
    • [346] nDNA adducts, breakage, damage,and mutation
    • [347] Genome integrity proteins and DNA Repair Enzymes (damaged by ROS)
    • [349] ROS in nucleus
    • [350] Gene expression is altered
    • [351] HMGB2 mRNA
    • [352] HMGB2 protein
    • [353] Glycation: sugars bond to nDNA and proteins
    • [354] Cytoplasmic tubulin accumulates in nucleus and damages chromatin
    • [357] Nrf2 activates antiox genes
    • [358] ZnT3 mRNA
    • [359] Spliceosome errors mis-splice Lamin-A and cytoskeleton mRNAs
    • [360] Progerin splice-variant of Lamin A accumulates
    • [361] Damaged nuclear proteins accumulate
    • [362] Loss of nuclear proteins
    • [363] Telomerase maintains Telomere Length
    • [364] Long Telomeres required for Stem Cell function
    • [365] Progerin shortens Telomeres
    • [366] Short telomeres cause splicing errors
    • [367] Methylation of Histones
    • [368] Activated NF-kB activates CD38
    • [369] NAD+ needed for PARP and sirtuin activity
    • [370] Retro-Transposable Elements (LINE-1) insert, mutate, break DNA
    • [371] Reverse Transcriptases mobilize RTEs
    • [372] Sirtuins deacetylate histones, and enhance DNA repair
    • [373] Sprouty-1 expressionn reduced by DNA methylation
    • ▼ [950] Environmental Factors
      • [709] X-Rays and ionizing radiation create ROS
      • [718] Smoke, etc. creates ROS
      • [725] Toxic Heavy Metals, Pb, Hg, Pesticides
      • [729] Pathogenic Infectious Agents, viruses, bacteria, microbes
      • [731] Chronic Psychological stress
      • [749] Chronic Periodontitis. Gingivitis bacteria increase production of A-beta
  • ▼ [809] Cell Nucleus Membrane
    • [034] ROS activate NF-kB, which enters nucleus, activating genes
    • [301] ZMPSTE24 converts pre-Lamin-A to Lamin-A
    • [355] Oxidized nuclear pore proteins allow other proteins in and out
    • [356] Signals to nucleus
  • ▼ [810] Endoplasmic Reticulum
    • [098] Misfolded proteins accumulate
    • ▼ [811] Endoplasmic Reticulum Membrane
      • [097] Oxidized membrane lipids and proteins release excess Ca2+

• ▼ [812] Whole Cells or Tissues
  • [127] Apop of articlular chondrocytes
  • [128] Trans-differentiation: Altered gene expression patterns change some cells to inappropriate phenotypes
  • [129] Fibroblast production of elastin
  • [130] Immune System and Apoptosis kill some cancer cells
  • [131] Arrested Cell Division: Short telomeres, altered nDNA, or damaged Lamins cause some cells to stop dividing
  • [132] Arrested Senescent cells secrete hormones, inflammatory cytokines, and toxins, which harm other cells
  • [133] Inflammatory cytokines (IL-6) induce expression of endothelial adhesion molecules
  • [134] Arrested Stem cells stop dividing
  • [135] Cell-to-cell Signaling pathways
  • [136] IL-6 causes neuronal precursors to become glial cells, not neurons
  • [137] Anergic T-cell clones accumulate and suppress naive T-cells
  • [138] Lung basal cells
  • [139] Stem cells replace some lost cells
  • [140] MSCs and functional fibroblasts
  • [141] Naive T-cell population shrinks, reducing ability to respond to infectious microbes
  • [142] Thymus size (involution)
  • [143] Satellite cell proliferation regenerates skeletal muscle
  • [144] Cardiac myocytes
  • [145] Skeletal muscle fibers
  • [146] Osteoblasts
  • [147] Motor neurons
  • [148] Cell Death: Apoptosis and necrosis kill important cells in slowly renewing tissues
  • [149] Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruct
  • [150] AGE signaling changes MSC Differentiation
  • [151] Healthy endocrine cells
  • [152] neocortex neurons and synapses
  • [153] Commanding neuroendocrine cells in hypothalamus
  • [154] neurons in SN
  • [155] Fibroblasts and MSCs repair ECM
  • [156] Neurotoxins destroy neurites, synapses, and neurons
  • [157] Neurogenesis by Adult Neural Stem Cells
  • [158] NGF and BDNF preserve neurons and improve synapses
  • [159] Macrophages bind to AGE-collagen
  • [160] Macrophages ingest peroxidized Lipids, LDL, and RBCs to become Foam Cells
  • [161] Cell detachment promotes metastasis
  • [162] Endothelium extravasates small clots and debris in capillaries
  • [164] NF-kB signaling by hypothalamic neurons
  • [165] TNFa secretion by microglia
  • [166] NF-kB activity in microglia
  • [167] Hypothalamic cells
  • [168] Brain Hyperactivity
  • [748] Macrophages digest LF - filled Exosomes .

• ▼ [900] Tissue, Organ, and Whole Body Physiology and Pathology
  • [901] Cancer
  • [903] Osteo- Arthritis
  • [904] Persistent, asymptomatic Infections, eg. CMV, occupy immune system
  • [905] Thin Skin; Thin Hair; White Hair.
  • [906] Macular Degeneration
  • [907] Blindness
  • [908] Retinopathy
  • [909] Stiff arteries and capillaries, systolic hypertension, cardiovascular disease
  • [910] Ischemic Stroke
  • [911] Atherosclerotic plaque buildup
  • [912] Heart Failure
  • [913] Heart Attack
  • [914] Hemorrhagic Stroke
  • [915] Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6
  • [916] Small clots in neural capillaries cause micro-strokes
  • [917] Impaired kidney function
  • [918] Reduced capacity of urinary Bladder
  • [919] Erectile Dysfunction
  • [920] Cataracts
  • [921] Stiff skin, tendons
  • [922] Lung Alveoli degraded
  • [923] Working memory and executive function
  • [924] Alzheimer's and other dementias
  • [925] Parkinson's Disease
  • [926] Osteoporosis
  • [927] Weakness, Frailty
  • [928] Sarcopenia
  • [929] Neuroendocrine and immune functions
  • [930] Pathogenic Infections kill cells and generate inflammation
  • [931] Menopause
  • [932] Impaired wound healing and tissue repair
  • [933] Pulmonary Emphysema, COPD
  • [934] Rheumatoid Arthritis
  • [935] Inflammation of Hypothalamus and skin
  • [936] GnRH improves Cognition, muscle strength, skin, bone, neurogenesis, memory
  • [937] Cardiac Hypertrophy, Stiff Heart
  • [938] Body Plan Dysregulation
  • [939] Failure to Regenerate
  • [940] Prostate Hyperplasia
  • [941] VCAM-1 in plasma
  • [999] Many other downstream effects of AGING

• ▼ [951] Intervention
  • [701] Enhance Mitochondrial Fission
  • [702] Lysosomal Enzyme Augmentation Therapy
  • [703] LF-formation Inhibitor Drugs
  • [704] LF-Removing Drugs
  • [705] Oral Spermidine or Agmatine
  • [706] Sirtuin Activators
  • [707] Epigenetic Reprograming (Yamanaka factors) Chromatin remodeling drugs.eg. HdAcs and HdAc inhibitors
  • [708] Telomerase and TERT Therapy and Activators
  • [710] Reprogramming, Genetic Engineering, Gene Editing: Increase expn of beneficial genes: eg TFAM, Lamp2a, hTERT, Lon Protease, Proteasome. Make super-fibroblasts. Re-differentiate certain cells for improved performance.
  • [711] R-alpha-Lipoic Acid reverses Nrf2 loss
  • [712] Splice Enhancement Therapy
  • [713] Selective T-Cell Deletion Therapy
  • [714] Stem Cell Therapy or Trophic Factors
  • [715] Glucose- Lowering Drugs
  • [716] Glycation -Inhibitor Drugs
  • [717] Enhance Detection and Turnover of mutant mtDNA
  • [719] Dietary or injected Antioxidants
  • [720] Fasting, CR, or Exercise reduce LDL levels
  • [721] PBT2, BBB-permeant metal ionophores
  • [722] TTR solublizing Drugs
  • [723] Crosslink- Breaker Drugs
  • [724] Stimulate or engineer super-Fibroblasts and MSCs to repair ECM
  • [726] Exercise or Hormone Therapy
  • [727] Fasting or CR or Drugs that mimic fasting
  • [728] Meditation
  • [730] Anti-Inflammatory Foods and Drugs including turmeric, Montelukast
  • [732] GnRH Injection
  • [733] Block NF-kB production
  • [734] Sleep
  • [735] Senolytic Drugs kill arrested cells to prevent spread of damage
  • [736] Infuse Young plasma or remove old plasma
  • [737] Nanoscavenger therapy cleans plasma
  • [738] Engineer cells to make anti-cancer immune cells
  • [740] 40 Hz flashingLight
  • [741] Gamma sound vibration
  • [742] J147 increases ATP. J147 induces NGF and BDNF, activates AMPK, inhibits mTOR,protects neurons from toxicity of glutamate and A-beta
  • [743] SM04554 stimulates hair growth in androgenic alopecia
  • [744] MK-0677
  • [745] Surgical shunt in cribiform plate
  • [746] Lanosterol
  • [747] Targeted Apoptotic Agents
  • [750] Elamipretide protects cardiolipin from ROS damage
  • [751] CD38 inhibitors
  • [752] Niacin, NMN, or NR supplements increase NAD+
  • [753] Reverse Transcriptase Inhibitors inhibit RTases
  • [754] Prostagladin PGE2 injection IM stimulates skeletal muscle stem cells