Denigma: Ontology

Ontology

Entities:

Lysosomes digest Junk, until they become filled with LF

ROS oxidize proteins & lipids

Free Fe, released by digestion, or trapped in LF, reacts with H2O2 to makeHO*.

Lamp2a imports tagged solumble cytoplasmic proteins

Oxidized, lipids, proteins, & Fe crosslink to form lipofuscin

LF - filled Lysosomes with damaged membranes spill lytic enzymes & reactive LF into cytoplasmk

Lipofuscin accumulates in Lysosomes of PM cells

ROS in Lysosomes cause damage to Lysosomal membranes or membrane scaffolding which controls vesicle fusions

H2O2 diffuses into Lysm

Autophagosome assembles. Engulfs damaged Lysms. Transports to new Lysm.

Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm.

Spermidine enhances apgy & decr histoneacetylation

Lipofuscin in cytoplasm can trigger Apoptosis

H2O2 in cytoplasm

H2O2 diffuses out of mito

Giant mitochondria accumulate when damage impairs mito fission. They canʼt be autophagized, & they produce more ROS.

ROS generated by mitochondrial metabolism

Mitochondrial Antioxidants quench some ROS

Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome.

mt ROS attack IMM, mt proteins, & mtDNA

Damaged mtDNA or replication machinery

mtDNA replication mistakes generate insertions, deletions

O2* - converted to H2O2 by SOD

Lon Protease digests damaged mt proteins

Lon Protease Levels decline with age.

ISC assy depends on memb pot.

mutant mtDNA

mt GPx degrades H2O2

Functionality of collective mt population

Rate of mito biogenesis

Clonal amplification of mutant mtDNA causes PM cell or skeletal muscle fiber segment to become anaerobic

Methyis on DNA

Acetylation of Histones

PGC-1α PGC-1β

LON Protease mRNA

Chromatin conformation is altered

Telomeres oxidized, damaged, or shortened

p53 rises

PARP-1 activated

Nuclear 2OS proteasome removes damaged proteins

Genome integrity proteins contain ISCs.

Telomere position effect alters gene exp

Dev Diffn reduces tase exp

chromosomes end-joining

nDNA adducts breakage damage & mutation

Genome integrity proteins & DNA repair Enzymes (damaged by ROS)

Levels of miRNA in brain change

ROS in nucleus

Gene expression is altered

HMGB2 mRNA

HMGB2 protein

Glycation: sugars bond to nDNA & proteins

Cytoplasmic tubulin accumulates in nucleus & damages chromatin

Oxidized nuclear pore proteins allow other proteins in & out

Signals to nucleus

Nrf2 activates antiox genes

ZnT3 MRNA

Spliceosomes error

Progerin splice-bariant of Lamin A accumulates

Damaged nuclear proteins accumulates

Loss of nuclear proteins

Catalase & cytosolic GPx degrade H2O2.

Redox potential poise in cytoplasm is incr by oxidation. This changes intracellular signaling & gene exp

Damaged Junk to be repaired or disassembled

Glycation: sugars, AGEs, & ALEs bond to intracellular proteins

Damaged proteasome subunits turnover by CMA

Junk molecules aggregate & crosslink if not quickly disassembled

Hyperphosphorylated Tau forms PHF, which bind Cu, produce H2O2

Proteasomes digest damaged cytoplasmic proteins

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

Tau hyperphosphorylation destabilizes microtubules, blocks Increase axon transport.

Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning

042 Aggs block & inhibit Proteasomes

Oxidized pigment enzymes in hair follicles turn hair white

Oxidized membrane lipids & proteins degrade transporters of Ca2+, Na+, Glu, & glucose; promote depolarization & Ca2+ influx

Reductive Hotspot: Anaerobic cells & muscle fiber segments export electrons through plasma membrane, generating extracellular ROS

Peroxidized Lipids & oxidized cholesterol in LDL are imported by other cells, & incorporated into membranes, damaging membranes & mitos via lipid chain-reactions

Normal Aβ in membrane reacts with Cu, producing H2O2 & ROS

Cytoplasmic antioxidants quench ROS

Endogenous Antioxidant Production

RAGE & Scavenger Receptors

Intracellular Ca2+ levels rise & generate ROS

Intraneuronal Fe generatesROS

Fe exported from neuron to EC transferrin

Low Zn makes neurons sick

Neuron Excitotoxicity

cAMP level in cytoplasm of PFC neurons

cAMP opens K+ channels, stops PFCNs from firing

Zn & Cu pumped into neurons by ZnT3

α2A receptors in PFCN membrane

Oxidized membrane lipids & proteins release excess Ca2+

Apop of articular chondrocytes

Redifferentiation: Altered gene expression patterns change some cells to inappropriate phenotypes

Fibroblast production of elastin

Immune System & Apoptosis kill some cancer cells

Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing.

Arrested cells secrete hormones, cytokines, & toxins, which harm other cells.

Inflammatory cytokines (IL-6) induce exp of endothelial adhesion molecules

Arrested Stem cells stop dividing

Cell-to-cell Signaling pathways

IL-6 causes neuronal precursors to become glial cells, not neurons

Anergic T-cell clones accumulate & suppress naive T-cells

Lung basal cells

Stem cells replace some lost cells

MSCs & functional fibroblasts

Naive T-cell population shrinks, reducing ability to respond to infectious microbes.

Thymus involutes

Sat cell proliferation regenerates skel muscle

Cardiac myocytes

Skeletal muscle fibres

Osteoblasts

Motor neurons

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction

AGE signaling changes MSC Diffn

Healthy endocrine cells

neocortex neurons & synapses

Commanding neuroendocrine cells in hypothalamus

neurons in SN

Fibroblasts & MSCs repair ECM

Neurotoxins destroy neurites, synapses & neurons

Neurogenesis by Adult Neural Stem Cells

BDNF preserves neurons & improves synapses

Macrophages bid to AGE-collagen

Macrophages ingest peroxidized Lipidsm LDL, & RBCs to become Foam Cells

Cell detachment promotes metasis

Endothelium extravasates small clots & debris in capillaries

Level of IL-15 & IL-15Rα in serum Neurogenesis by Adult Neural Stem Cells Chemokines, incl CCL11, in plasma & CSF 229 157

Glucose Concentration in Bloodstream. (Moderate in healthy people; higher in Diabetes)

Glycation: sugars bond to extracellular proteins

Glycated extracellular proteins form AGEs and crosslinks

Igs crosslink to kidney glomerular BM causing complement mediated damage

Glycated Arginine can convert to Ornithine

Altered Arg & Asp residues disrupt RGD cell attachment

ECM protein residues can deamidate or isomerize, which might change folding

Extracellular ROS

ROS & sugars peroxidize lipids & glycate proteins in circulating LDL

Aβ oxidizes cholesterol & fatty acids, generates H2O2 & OH* radicals

Antioxidants in EC fluids quench ROS

Aβ monomers aggregate with Zn, Cu, to form toxic Aβ oligos & plaques

metal ionophores disaggregate toxic Αβ oligos. take Cu, Zn and release Αβ monomer

Cu, Zn & Αβ monomer released into glutamatergic synapses during neurotransmission

EC Zn

Metal Ionophores take Cu, Zn into neuron

Αβ monomer slowly cleared by transport to urine

MMP2 & 3 slowly digest Αβ monomer

Zn/Cu activate MMP2&3

Glycated LDL and RBCs crosslink to endothelial arterial collagen

Ca++ & Lipids bound to elastin

Oxidation & cleavage of ECM proteins

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment

brown

TTR-amyloid in muscle & elsewhere

Cerebral amyloid angiopathy decreases endothelial health

Good Hormone Levels

Chemokines, incl CCL11, in plasma & CSF levels in sat cell niche BM & blood

EGF, FGF FGF

TGFβ Inhibition of Pathway or Process

MMPs secreted by arrested cells

Hypochlorous acid secreted by inflam macrophages

Articlular cartilage deteriorates

Enhance Mitochondrial Fission

Lysosomal Enzyme Augmentation Therapy

LH-Formation Inhibitor Drugs

LF-Removing Drugs

Oral Spermidine

Sirtuin Activators

Chromatin remodeling drugs. eg. HdAcs & HdAc inhibitors

Telomerase Therapy & Activators

X-rays & ionizing radiation create ROS

Increase exp of beneficial genes eg lamp2a, Lon Protease, Proteasome, hTERT

R-α−Lipoic acid reverses Nrf2 loss

Splice Enhancement Therapy

Selective T-Cell Deletion Therapy

Stem Cell Therapy or Trophic Factors

Glucose-LoweringDrugs

Glycation-Inhibitor Drugs

Enhance Detection & Turnover of mutant mtDNA

Smoke, etc. creates ROS

Dietary or injected Antioxidants

Fasting, CR or Exercise reduce LDL levels

BBBpermeant metal ionophores

TTR solublizing Drugs

Crosslink-Breaker Drugs

Stimulate Fibroblast & MSC repair of ECM

Toxic heavy Metals Pb, Hg, Pesticides

Exercise or Hormone Therapy

Fasting or CR or Drugs that mimic fasting

Meditation

Pathogenic Infectious Agents, viruses, bacteria, microbes

Anti-Inflammatory Foods & Drugs

Psychological Stress

Tissue Organ, & Whole Body: Physiology & Pathology

Cancer

Osteo- Arthritis

Persistent, asymptomatic Infections, eg. CMV, occupy immune system

Thin Skin; Thin Hair; White Hair.

Macular Degeneration

Blindness

Retinopathy

Stiff arteries & capilaries, systolic hypertension, cardiovascular disease

Ischemic Stroke

Atherosclerotic plaque buildup

Heart Failure

Heart Attack

Hemorrhagic Stroke

Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6.

Small clots in neural capillaries cause micro-strokes

Impaired kidney function.

Reduced capacity of urinary Bladder

Erectile Dysfunction

Cataracts

Stiff skin, tendons

Lung Alveoli degraded

Working memory & exec function decline

Alzheimerʼs & related Dementias

Neuroendocrine & immune functions degrade

Pathogenic Infections kill cells & generate inflammation

Menopause

Impaired wound healing & tissue repair

Pulmonary Emphysema, COPD

Rheumatoid Arthritis

Many other downstream effects of AGING

Misfolded proteins accumulate

Relations:

Lysosomal Enzyme Augmentation Therapy -pink-> Lysosomes digest Junk, until they become filled with LF

Lysosomal Enzyme Augmentation Therapy -pink-> Oxidized, lipids, proteins, & Fe crosslink to form lipofuscin

LH-Formation Inhibitor Drugs -pink-> Oxidized, lipids, proteins, & Fe crosslink to form lipofuscin

LF-Removing Drugs -pink-> Lipofuscin accumulates in Lysosomes of PM cells

Lysosomes digest Junk, until they become filled with LF -red-> ROS oxidize proteins & lipids

Lysosomes digest Junk, until they become filled with LF -red-> Free Fe, released by digestion, or trapped in LF, reacts with H2O2 to makeHO*.

ROS oxidize proteins & lipids -red-> Oxidized, lipids, proteins, & Fe crosslink to form lipofuscin

Free Fe, released by digestion, or trapped in LF, reacts with H2O2 to makeHO*. -red-> ROS oxidize proteins & lipids

Free Fe, released by digestion, or trapped in LF, reacts with H2O2 to makeHO*. -red-> Oxidized, lipids, proteins, & Fe crosslink to form lipofuscin

Free Fe, released by digestion, or trapped in LF, reacts with H2O2 to makeHO*. -red-> ROS in Lysosomes cause damage to Lysosomal membranes or membrane scaffolding which controls vesicle fusions

LF - filled Lysms have reduced capac & 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. -pink-> Autophagosome assembles. Engulfs damaged Lysms. Transports to new Lysm.

LF - filled Lysms have reduced capac & 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. -yellow-> Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning

LF - filled Lysms have reduced capac & 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. -red-> Lysosomes digest Junk, until they become filled with LF

Lamp2a imports tagged solumble cytoplasmic proteins -pink-> Lysosomes digest Junk, until they become filled with LF

Oxidized, lipids, proteins, & Fe crosslink to form lipofuscin -red-> Lipofuscin accumulates in Lysosomes of PM cells

LF - filled Lysosomes with damaged membranes spill lytic enzymes & reactive LF into cytoplasmk -red-> Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning

LF - filled Lysosomes with damaged membranes spill lytic enzymes & reactive LF into cytoplasmk -red-> Lipofuscin in cytoplasm can trigger Apoptosis

Lipofuscin accumulates in Lysosomes of PM cells -red-> LF - filled Lysms have reduced capac & 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.

Lipofuscin accumulates in Lysosomes of PM cells -red-> LF - filled Lysosomes with damaged membranes spill lytic enzymes & reactive LF into cytoplasmk

Lipofuscin accumulates in Lysosomes of PM cells -red-> Free Fe, released by digestion, or trapped in LF, reacts with H2O2 to makeHO*.

ROS in Lysosomes cause damage to Lysosomal membranes or membrane scaffolding which controls vesicle fusions -red-> LF - filled Lysosomes with damaged membranes spill lytic enzymes & reactive LF into cytoplasmk

H2O2 diffuses into Lysm -red-> Free Fe, released by digestion, or trapped in LF, reacts with H2O2 to makeHO*.

Autophagosome assembles. Engulfs damaged Lysms. Transports to new Lysm. -pink-> ROS in Lysosomes cause damage to Lysosomal membranes or membrane scaffolding which controls vesicle fusions

Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm. -pink-> Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome.

Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm. -pink-> Fibroblasts & MSCs repair ECM

Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm. -pink-> Damaged Junk to be repaired or disassembled

Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm. -pink-> Oxidized nuclear pore proteins allow other proteins in & out

Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm. -pink-> Progerin splice-bariant of Lamin A accumulates

Spermidine enhances apgy & decr histoneacetylation -yellow-> Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm.

Spermidine enhances apgy & decr histoneacetylation -blue-> p53 rises

Lipofuscin in cytoplasm can trigger Apoptosis -red-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

H2O2 in cytoplasm -red-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

H2O2 in cytoplasm -red-> H2O2 diffuses into Lysm

H2O2 diffuses out of mito -red-> H2O2 in cytoplasm

H2O2 diffuses out of mito -red-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

Giant mitochondria accumulate when damage impairs mito fission. They canʼt be autophagized, & they produce more ROS. -blue-> Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning

Giant mitochondria accumulate when damage impairs mito fission. They canʼt be autophagized, & they produce more ROS. -black-> ISC assy depends on memb pot.

Giant mitochondria accumulate when damage impairs mito fission. They canʼt be autophagized, & they produce more ROS. -black-> Functionality of collective mt population

Giant mitochondria accumulate when damage impairs mito fission. They canʼt be autophagized, & they produce more ROS. -red-> ROS generated by mitochondrial metabolism

ROS generated by mitochondrial metabolism -red-> O2* - converted to H2O2 by SOD

ROS generated by mitochondrial metabolism -red-> mt ROS attack IMM, mt proteins, & mtDNA

Mitochondrial Antioxidants quench some ROS -green-> ROS generated by mitochondrial metabolism

Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome. -pink-> Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm.

Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome. -black-> ISC assy depends on memb pot.

Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome. -blue-> Functionality of collective mt population

Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome. -black-> Giant mitochondria accumulate when damage impairs mito fission. They canʼt be autophagized, & they produce more ROS.

mt ROS attack IMM, mt proteins, & mtDNA -red-> Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome.

mt ROS attack IMM, mt proteins, & mtDNA -red-> Damaged mtDNA or replication machinery

Damaged mtDNA or replication machinery -blue-> mutant mtDNA

mtDNA replication mistakes generate insertions, deletions -blue-> mutant mtDNA

O2* - converted to H2O2 by SOD -red-> H2O2 diffuses out of mito

Lon Protease digests damaged mt proteins -pink-> Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome.

Lon Protease digests damaged mt proteins -pink-> Damaged mtDNA or replication machinery

Lon Protease Levels decline with age. -pink-> Lon Protease digests damaged mt proteins

ISC assy depends on memb pot. -blue-> Genome integrity proteins contain ISCs.

mutant mtDNA -blue-> Clonal amplification of mutant mtDNA causes PM cell or skeletal muscle fiber segment to become anaerobic

mutant mtDNA -blue-> Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome.

mt GPx degrades H2O2 -green-> O2* - converted to H2O2 by SOD

Functionality of collective mt population -blue-> Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction

Rate of mito biogenesis -blue-> Functionality of collective mt population

Clonal amplification of mutant mtDNA causes PM cell or skeletal muscle fiber segment to become anaerobic -blue-> Reductive Hotspot: Anaerobic cells & muscle fiber segments export electrons through plasma membrane, generating extracellular ROS

Clonal amplification of mutant mtDNA causes PM cell or skeletal muscle fiber segment to become anaerobic -blue-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

Glucose Concentration in Bloodstream. (Moderate in healthy people; higher in Diabetes) -brown-> Glycation: sugars bond to extracellular proteins

Glucose-LoweringDrugs -green-> Glucose Concentration in Bloodstream. (Moderate in healthy people; higher in Diabetes)

Level of IL-15 & IL-15Rα in serum Neurogenesis by Adult Neural Stem Cells Chemokines, incl CCL11, in plasma & CSF 229 157 -purple-> Rate of mito biogenesis

Glycated extracellular proteins form AGEs and crosslinks -brown-> Igs crosslink to kidney glomerular BM causing complement mediated damage

Glycated extracellular proteins form AGEs and crosslinks -brown-> RAGE & Scavenger Receptors

Glycated extracellular proteins form AGEs and crosslinks -red-> Glycated Arginine can convert to Ornithine

Glycated extracellular proteins form AGEs and crosslinks -red-> Altered Arg & Asp residues disrupt RGD cell attachment

Glycated extracellular proteins form AGEs and crosslinks -red-> ROS & sugars peroxidize lipids & glycate proteins in circulating LDL

Glycation: sugars bond to extracellular proteins -red-> Glycated extracellular proteins form AGEs and crosslinks

Glycation-Inhibitor Drugs -green-> Glycation: sugars bond to extracellular proteins

Igs crosslink to kidney glomerular BM causing complement mediated damage -brown-> Impaired kidney function.

Enhance Detection & Turnover of mutant mtDNA -green-> Clonal amplification of mutant mtDNA causes PM cell or skeletal muscle fiber segment to become anaerobic

Glycated Arginine can convert to Ornithine -red-> Altered Arg & Asp residues disrupt RGD cell attachment

Reductive Hotspot: Anaerobic cells & muscle fiber segments export electrons through plasma membrane, generating extracellular ROS -red-> Extracellular ROS

Altered Arg & Asp residues disrupt RGD cell attachment -purple-> Cell detachment promotes metasis

Altered Arg & Asp residues disrupt RGD cell attachment -purple-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

Extracellular ROS -red-> Oxidation & cleavage of ECM proteins

Extracellular ROS -red-> ROS & sugars peroxidize lipids & glycate proteins in circulating LDL

ECM protein residues can deamidate or isomerize, which might change folding -red-> Altered Arg & Asp residues disrupt RGD cell attachment

ECM protein residues can deamidate or isomerize, which might change folding -red-> Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment

Smoke, etc. creates ROS -red-> Extracellular ROS

Dietary or injected Antioxidants -green-> Mitochondrial Antioxidants quench some ROS

Dietary or injected Antioxidants -green-> Cytoplasmic antioxidants quench ROS

Dietary or injected Antioxidants -green-> Antioxidants in EC fluids quench ROS

Peroxidized Lipids & oxidized cholesterol in LDL are imported by other cells, & incorporated into membranes, damaging membranes & mitos via lipid chain-reactions -tan-> Damaged mitos produce less ATP & more ROS; have lower memb pot. Most are autophagized to Lysosome.

Peroxidized Lipids & oxidized cholesterol in LDL are imported by other cells, & incorporated into membranes, damaging membranes & mitos via lipid chain-reactions -tan-> Redox potential poise in cytoplasm is incr by oxidation. This changes intracellular signaling & gene exp

Peroxidized Lipids & oxidized cholesterol in LDL are imported by other cells, & incorporated into membranes, damaging membranes & mitos via lipid chain-reactions -tan-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

Peroxidized Lipids & oxidized cholesterol in LDL are imported by other cells, & incorporated into membranes, damaging membranes & mitos via lipid chain-reactions -brown-> Macrophages ingest peroxidized Lipidsm LDL, & RBCs to become Foam Cells

ROS & sugars peroxidize lipids & glycate proteins in circulating LDL -red-> Peroxidized Lipids & oxidized cholesterol in LDL are imported by other cells, & incorporated into membranes, damaging membranes & mitos via lipid chain-reactions

ROS & sugars peroxidize lipids & glycate proteins in circulating LDL -red-> Glycated LDL and RBCs crosslink to endothelial arterial collagen

Fasting, CR or Exercise reduce LDL levels -green-> Peroxidized Lipids & oxidized cholesterol in LDL are imported by other cells, & incorporated into membranes, damaging membranes & mitos via lipid chain-reactions

Normal Aβ in membrane reacts with Cu, producing H2O2 & ROS -red-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

Normal Aβ in membrane reacts with Cu, producing H2O2 & ROS -brown-> Cu, Zn & Αβ monomer released into glutamatergic synapses during neurotransmission

Aβ oxidizes cholesterol & fatty acids, generates H2O2 & OH* radicals -red-> Extracellular ROS

Aβ oxidizes cholesterol & fatty acids, generates H2O2 & OH* radicals -black-> neocortex neurons & synapses

Aβ oxidizes cholesterol & fatty acids, generates H2O2 & OH* radicals -red-> Peroxidized Lipids & oxidized cholesterol in LDL are imported by other cells, & incorporated into membranes, damaging membranes & mitos via lipid chain-reactions

Antioxidants in EC fluids quench ROS -green-> Extracellular ROS

Antioxidants in EC fluids quench ROS -green-> Aβ oxidizes cholesterol & fatty acids, generates H2O2 & OH* radicals

Antioxidants in EC fluids quench ROS -green-> RAGE & Scavenger Receptors

RAGE & Scavenger Receptors -purple-> AGE signaling changes MSC Diffn

RAGE & Scavenger Receptors -purple-> Macrophages bid to AGE-collagen

RAGE & Scavenger Receptors -purple-> Macrophages ingest peroxidized Lipidsm LDL, & RBCs to become Foam Cells

Fe exported from neuron to EC transferrin -green-> Intraneuronal Fe generatesROS

EC Zn -black-> Fe exported from neuron to EC transferrin

Cu, Zn & Αβ monomer released into glutamatergic synapses during neurotransmission -brown-> Aβ monomers aggregate with Zn, Cu, to form toxic Aβ oligos & plaques

Cu, Zn & Αβ monomer released into glutamatergic synapses during neurotransmission -brown-> EC Zn

Cu, Zn & Αβ monomer released into glutamatergic synapses during neurotransmission -pink-> Metal Ionophores take Cu, Zn into neuron

Cu, Zn & Αβ monomer released into glutamatergic synapses during neurotransmission -brown-> Cerebral amyloid angiopathy decreases endothelial health

Aβ monomers aggregate with Zn, Cu, to form toxic Aβ oligos & plaques -pink-> Αβ monomer slowly cleared by transport to urine

Aβ monomers aggregate with Zn, Cu, to form toxic Aβ oligos & plaques -red-> Aβ oxidizes cholesterol & fatty acids, generates H2O2 & OH* radicals

Aβ monomers aggregate with Zn, Cu, to form toxic Aβ oligos & plaques -pink-> Metal Ionophores take Cu, Zn into neuron

metal ionophores disaggregate toxic Αβ oligos. take Cu, Zn and release Αβ monomer -pink-> Aβ monomers aggregate with Zn, Cu, to form toxic Aβ oligos & plaques

Zn & Cu pumped into neurons by ZnT3 -pink-> Zn supply in neurons

Metal Ionophores take Cu, Zn into neuron -pink-> Zn supply in neurons

Αβ monomer slowly cleared by transport to urine -pink-> Aβ monomers aggregate with Zn, Cu, to form toxic Aβ oligos & plaques

BBBpermeant metal ionophores -pink-> Metal Ionophores take Cu, Zn into neuron

BBBpermeant metal ionophores -pink-> metal ionophores disaggregate toxic Αβ oligos. take Cu, Zn and release Αβ monomer

α2A receptors in PFCN membrane -purple-> cAMP level in cytoplasm of PFC neurons

Zn/Cu activate MMP2&3 -black-> MMP2 & 3 slowly digest Αβ monomer

MMP2 & 3 slowly digest Αβ monomer -pink-> Aβ monomers aggregate with Zn, Cu, to form toxic Aβ oligos & plaques

EGF, FGF FGF -purple-> MAPK pERK signaling

Glycated LDL and RBCs crosslink to endothelial arterial collagen -black-> Atherosclerotic plaque buildup

Ca++ & Lipids bound to elastin -brown-> Oxidation & cleavage of ECM proteins

TGFβ Inhibition of Pathway or Process -red-> Sat cell proliferation regenerates skel muscle

Chemokines, incl CCL11, in plasma & CSF levels in sat cell niche BM & blood -red-> Neurogenesis by Adult Neural Stem Cells

MMPs secreted by arrested cells -brown-> Oxidation & cleavage of ECM proteins

Oxidation & cleavage of ECM proteins -red-> brown

Oxidation & cleavage of ECM proteins -red-> Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment

TTR solublizing Drugs -pink-> TTR-amyloid in muscle & elsewhere

Hypochlorous acid secreted by inflam macrophages -red-> Oxidation & cleavage of ECM proteins

Articlular cartilage deteriorates -brown-> Osteo- Arthritis

Good Hormone Levels -purple-> Signals to nucleus

Good Hormone Levels -purple-> Neuroendocrine & immune functions degrade

Cerebral amyloid angiopathy decreases endothelial health -black-> Endothelium extravasates small clots & debris in capillaries

Cerebral amyloid angiopathy decreases endothelial health -black-> Hemorrhagic Stroke

TTR-amyloid in muscle & elsewhere -brown-> Impaired kidney function.

TTR-amyloid in muscle & elsewhere -brown-> Heart Failure

brown -brown-> Stiff arteries & capilaries, systolic hypertension, cardiovascular disease

brown -brown-> Lung Alveoli degraded

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Macrophages bid to AGE-collagen

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Impaired wound healing & tissue repair

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Stiff skin, tendons

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Cataracts

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Impaired kidney function.

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Rheumatoid Arthritis

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6.

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Stiff arteries & capilaries, systolic hypertension, cardiovascular disease

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Reduced capacity of urinary Bladder

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Erectile Dysfunction

Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment -brown-> Atherosclerotic plaque buildup

Crosslink-Breaker Drugs -pink-> Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment

Oral Spermidine -green-> Spermidine enhances apgy & decr histoneacetylation

Sirtuin Activators -green-> Acetylation of Histones

Methyis on DNA -blue-> Chromatin conformation is altered

Acetylation of Histones -blue-> Chromatin conformation is altered

PGC-1α PGC-1β -blue-> Rate of mito biogenesis

LON Protease mRNA -green-> H2O2 in cytoplasm

Redox potential poise in cytoplasm is incr by oxidation. This changes intracellular signaling & gene exp -purple-> Chromatin conformation is altered

Redox potential poise in cytoplasm is incr by oxidation. This changes intracellular signaling & gene exp -purple-> Signals to nucleus

Redox potential poise in cytoplasm is incr by oxidation. This changes intracellular signaling & gene exp -purple-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

Redox potential poise in cytoplasm is incr by oxidation. This changes intracellular signaling & gene exp -purple-> Clonal amplification of mutant mtDNA causes PM cell or skeletal muscle fiber segment to become anaerobic

Damaged Junk to be repaired or disassembled -pink-> Lamp2a imports tagged solumble cytoplasmic proteins

Damaged Junk to be repaired or disassembled -pink-> Autophagosome assembles. Engulfs junk, old mitos, organelles, psomes, ribosomes, damaged membranes & nuclear scaffolding. Transports to Lysm.

Damaged Junk to be repaired or disassembled -pink-> Proteasomes digest damaged cytoplasmic proteins

Damaged Junk to be repaired or disassembled -tan-> Junk molecules aggregate & crosslink if not quickly disassembled

Glycation: sugars, AGEs, & ALEs bond to intracellular proteins -tan-> Damaged Junk to be repaired or disassembled

Damaged proteasome subunits turnover by CMA -pink-> Lamp2a imports tagged solumble cytoplasmic proteins

Damaged proteasome subunits turnover by CMA -pink-> Proteasomes digest damaged cytoplasmic proteins

Misfolded proteins accumulate -black-> Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction

Oxidized membrane lipids & proteins release excess Ca2+ -tan-> Intracellular Ca2+ levels rise & generate ROS

Oxidized membrane lipids & proteins release excess Ca2+ -red-> Sarcopenia

Chromatin remodeling drugs. eg. HdAcs & HdAc inhibitors -blue-> Chromatin conformation is altered

Chromatin conformation is altered -blue-> Gene expression is altered

PARP-1 activated -blue-> Chromatin conformation is altered

PARP-1 activated -black-> Nuclear 2OS proteasome removes damaged proteins

PARP-1 activated -blue-> Genome integrity proteins & DNA repair Enzymes (damaged by ROS)

Nuclear 2OS proteasome removes damaged proteins -pink-> Genome integrity proteins & DNA repair Enzymes (damaged by ROS)

Nuclear 2OS proteasome removes damaged proteins -pink-> Damaged nuclear proteins accumulates

Genome integrity proteins contain ISCs. -green-> Genome integrity proteins & DNA repair Enzymes (damaged by ROS)

Junk molecules aggregate & crosslink if not quickly disassembled -tan-> Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning

Proteasomes digest damaged cytoplasmic proteins -pink-> Damaged proteasome subunits turnover by CMA

Proteasomes digest damaged cytoplasmic proteins -green-> Damaged Junk to be repaired or disassembled

Cytoplasmic antioxidants quench ROS -green-> Misfolded proteins accumulate

Cytoplasmic antioxidants quench ROS -green-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

Endogenous Antioxidant Production -green-> Cytoplasmic antioxidants quench ROS

Telomeres oxidized, damaged, or shortened -blue-> PARP-1 activated

Telomeres oxidized, damaged, or shortened -blue-> Glycation: sugars bond to nDNA & proteins

Telomeres oxidized, damaged, or shortened -blue-> Spliceosomes error

Telomeres oxidized, damaged, or shortened -blue-> p53 rises

Telomeres oxidized, damaged, or shortened -blue-> chromosomes end-joining

p53 rises -blue-> Spliceosomes error

p53 rises -blue-> PGC-1α PGC-1β

Telomerase Therapy & Activators -green-> Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing.

Telomerase Therapy & Activators -green-> Telomeres oxidized, damaged, or shortened

Telomere position effect alters gene exp -blue-> Gene expression is altered

Dev Diffn reduces tase exp -blue-> Telomeres oxidized, damaged, or shortened

chromosomes end-joining -blue-> nDNA adducts breakage damage & mutation

nDNA adducts breakage damage & mutation -blue-> p53 rises

nDNA adducts breakage damage & mutation -blue-> chromosomes end-joining

nDNA adducts breakage damage & mutation -blue-> Gene expression is altered

nDNA adducts breakage damage & mutation -black-> PARP-1 activated

nDNA adducts breakage damage & mutation -blue-> Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing.

nDNA adducts breakage damage & mutation -blue-> Cancer

Genome integrity proteins & DNA repair Enzymes (damaged by ROS) -green-> nDNA adducts breakage damage & mutation

Hyperphosphorylated Tau forms PHF, which bind Cu, produce H2O2 -red-> H2O2 in cytoplasm

Hyperphosphorylated Tau forms PHF, which bind Cu, produce H2O2 -red-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

X-rays & ionizing radiation create ROS -red-> ROS in nucleus

X-rays & ionizing radiation create ROS -red-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

Levels of miRNA in brain change -blue-> Gene expression is altered

ROS in nucleus -red-> nDNA adducts breakage damage & mutation

ROS in nucleus -red-> Genome integrity proteins & DNA repair Enzymes (damaged by ROS)

ROS in nucleus -red-> Oxidized nuclear pore proteins allow other proteins in & out

ROS in nucleus -red-> Glycation: sugars bond to nDNA & proteins

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Damaged Junk to be repaired or disassembled

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Misfolded proteins accumulate

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Oxidized membrane lipids & proteins release excess Ca2+

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Proteasomes digest damaged cytoplasmic proteins

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Normal Aβ in membrane reacts with Cu, producing H2O2 & ROS

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Oxidized membrane lipids & proteins degrade transporters of Ca2+, Na+, Glu, & glucose; promote depolarization & Ca2+ influx

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Oxidized pigment enzymes in hair follicles turn hair white

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Oxidized nuclear pore proteins allow other proteins in & out

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> ROS in nucleus

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Redox potential poise in cytoplasm is incr by oxidation. This changes intracellular signaling & gene exp

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Catalase & cytosolic GPx degrade H2O2.

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> H2O2 in cytoplasm

Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated. -red-> Damaged Junk to be repaired or disassembled

Increase exp of beneficial genes eg lamp2a, Lon Protease, Proteasome, hTERT -blue-> Gene expression is altered

Gene expression is altered -blue-> HMGB2 mRNA

Gene expression is altered -blue-> ZnT3 MRNA

Gene expression is altered -blue-> Redifferentiation: Altered gene expression patterns change some cells to inappropriate phenotypes

Gene expression is altered -blue-> Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing.

Gene expression is altered -blue-> Cancer

Gene expression is altered -blue-> Nrf2 activates antiox genes

Gene expression is altered -blue-> Dev Diffn reduces tase exp

Gene expression is altered -blue-> LON Protease mRNA

HMGB2 mRNA -blue-> HMGB2 protein

HMGB2 protein -black-> Apop of articular chondrocytes

Glycation: sugars bond to nDNA & proteins -red-> nDNA adducts breakage damage & mutation

Glycation: sugars bond to nDNA & proteins -red-> Damaged nuclear proteins accumulates

Cytoplasmic tubulin accumulates in nucleus & damages chromatin -blue-> nDNA adducts breakage damage & mutation

Cytoplasmic tubulin accumulates in nucleus & damages chromatin -blue-> Damaged nuclear proteins accumulates

Oxidized nuclear pore proteins allow other proteins in & out -blue-> Oxidized nuclear pore proteins allow other proteins in & out

Tau hyperphosphorylation destabilizes microtubules, blocks Increase axon transport. -black-> Hyperphosphorylated Tau forms PHF, which bind Cu, produce H2O2

Tau hyperphosphorylation destabilizes microtubules, blocks Increase axon transport. -black-> neocortex neurons & synapses

Tau hyperphosphorylation destabilizes microtubules, blocks Increase axon transport. -tan-> Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning

Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning -red-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning -red-> 042 Aggs block & inhibit Proteasomes

Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning -tan-> Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction

Reactive Aggs, giant mitochondria, & LF-filled Lysosomes accumulate in cytoplasm, generate ROS, & impaircell functioning -tan-> Macular Degeneration

042 Aggs block & inhibit Proteasomes -red-> Proteasomes digest damaged cytoplasmic proteins

Intracellular Ca2+ levels rise & generate ROS -purple-> Neuron Excitotoxicity

Intraneuronal Fe generatesROS -red-> Cytoplasmic ROS attack intracellular & membrane proteins & lipids. Enzymes & proteasomes get inactivated.

Intraneuronal Fe generatesROS -tan-> Fe exported from neuron to EC transferrin

R-α−Lipoic acid reverses Nrf2 loss -green-> Nrf2 activates antiox genes

Nrf2 activates antiox genes -green-> Endogenous Antioxidant Production

Signals to nucleus -purple-> Progerin splice-bariant of Lamin A accumulates

Splice Enhancement Therapy -blue-> Spliceosomes error

Spliceosomes error -blue-> Progerin splice-bariant of Lamin A accumulates

Damaged nuclear proteins accumulates -black-> Telomeres oxidized, damaged, or shortened

Damaged nuclear proteins accumulates -black-> Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing.

Damaged nuclear proteins accumulates -blue-> Damaged nuclear proteins accumulates

Loss of nuclear proteins -blue-> Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing.

Oxidized pigment enzymes in hair follicles turn hair white -black-> Thin Skin; Thin Hair; White Hair.

Oxidized membrane lipids & proteins degrade transporters of Ca2+, Na+, Glu, & glucose; promote depolarization & Ca2+ influx -tan-> Intracellular Ca2+ levels rise & generate ROS

Neuron Excitotoxicity -black-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

Low Zn makes neurons sick -black-> Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction

Low Zn makes neurons sick -black-> Alzheimerʼs & related Dementias

Notch receptor -black-> Sat cell proliferation regenerates skel muscle

MAPK pERK signaling -purple-> Delta Ligand

Delta Ligand -purple-> Notch receptor

cAMP level in cytoplasm of PFC neurons -purple-> cAMP opens K+ channels, stops PFCNs from firing

cAMP opens K+ channels, stops PFCNs from firing -black-> Working memory & exec function decline

Selective T-Cell Deletion Therapy -green-> Anergic T-cell clones accumulate & suppress naive T-cells

Stem Cell Therapy or Trophic Factors -green-> Stem cells replace some lost cells

Stem Cell Therapy or Trophic Factors -green-> Arrested Stem cells stop dividing

Stem Cell Therapy or Trophic Factors -green-> Menopause

Stem Cell Therapy or Trophic Factors -green-> Rheumatoid Arthritis

Redifferentiation: Altered gene expression patterns change some cells to inappropriate phenotypes -black-> Fibroblast production of elastin

Redifferentiation: Altered gene expression patterns change some cells to inappropriate phenotypes -black-> Many other downstream effects of AGING

Fibroblast production of elastin -black-> Stiff skin, tendons

Fibroblast production of elastin -black-> Stiff arteries & capilaries, systolic hypertension, cardiovascular disease

Immune System & Apoptosis kill some cancer cells -green-> Cancer

Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing. -black-> Arrested cells secrete hormones, cytokines, & toxins, which harm other cells.

Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing. -black-> Arrested Stem cells stop dividing

Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing. -black-> Fibroblast production of elastin

Arrested Cell Division: Short telomeres, 131 altered nDNA, or damaged Lamins cause some cells to stop dividing. -brown-> MMPs secreted by arrested cells

Arrested cells secrete hormones, cytokines, & toxins, which harm other cells. -purple-> Redifferentiation: Altered gene expression patterns change some cells to inappropriate phenotypes

Arrested cells secrete hormones, cytokines, & toxins, which harm other cells. -purple-> Fibroblast production of elastin

Arrested cells secrete hormones, cytokines, & toxins, which harm other cells. -purple-> Cancer

Arrested cells secrete hormones, cytokines, & toxins, which harm other cells. -purple-> Inflammatory cytokines (IL-6) induce exp of endothelial adhesion molecules

Arrested cells secrete hormones, cytokines, & toxins, which harm other cells. -purple-> IL-6 causes neuronal precursors to become glial cells, not neurons

Arrested cells secrete hormones, cytokines, & toxins, which harm other cells. -purple-> Cell-to-cell Signaling pathways

Inflammatory cytokines (IL-6) induce exp of endothelial adhesion molecules -purple-> Atherosclerotic plaque buildup

Inflammatory cytokines (IL-6) induce exp of endothelial adhesion molecules -purple-> Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6.

Arrested Stem cells stop dividing -black-> Stiff arteries & capilaries, systolic hypertension, cardiovascular disease

Arrested Stem cells stop dividing -black-> Thin Skin; Thin Hair; White Hair.

Arrested Stem cells stop dividing -black-> Neuroendocrine & immune functions degrade

Arrested Stem cells stop dividing -black-> MSCs & functional fibroblasts

Arrested Stem cells stop dividing -black-> Lung basal cells

Arrested Stem cells stop dividing -black-> Stem cells replace some lost cells

Cell-to-cell Signaling pathways -purple-> Signals to nucleus

IL-6 causes neuronal precursors to become glial cells, not neurons -black-> neocortex neurons & synapses

IL-6 causes neuronal precursors to become glial cells, not neurons -black-> Motor neurons

IL-6 causes neuronal precursors to become glial cells, not neurons -black-> Skeletal muscle fibres

Anergic T-cell clones accumulate & suppress naive T-cells -black-> Naive T-cell population shrinks, reducing ability to respond to infectious microbes.

Lung basal cells -black-> Pulmonary Emphysema, COPD

Stem cells replace some lost cells -green-> Sat cell proliferation regenerates skel muscle

Stem cells replace some lost cells -green-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

MSCs & functional fibroblasts -green-> Fibroblast production of elastin

MSCs & functional fibroblasts -green-> Fibroblasts & MSCs repair ECM

MSCs & functional fibroblasts -black-> Osteoblasts

MSCs & functional fibroblasts -black-> Impaired wound healing & tissue repair

MSCs & functional fibroblasts -black-> Pulmonary Emphysema, COPD

MSCs & functional fibroblasts -black-> Thin Skin; Thin Hair; White Hair.

Naive T-cell population shrinks, reducing ability to respond to infectious microbes. -black-> Pathogenic Infections kill cells & generate inflammation

Naive T-cell population shrinks, reducing ability to respond to infectious microbes. -black-> Neuroendocrine & immune functions degrade

Thymus involutes -black-> Naive T-cell population shrinks, reducing ability to respond to infectious microbes.

Thymus involutes -black-> Neuroendocrine & immune functions degrade

Sat cell proliferation regenerates skel muscle -green-> Skeletal muscle fibres

Cardiac myocytes -black-> Heart Failure

Skeletal muscle fibres -black-> Sarcopenia

Osteoblasts -black-> Osteoporosis

Motor neurons -black-> Skeletal muscle fibres

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> Apop of articular chondrocytes

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> Healthy endocrine cells

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> neocortex neurons & synapses

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> neurons in SN

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> Commanding neuroendocrine cells in hypothalamus

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> Motor neurons

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> Cardiac myocytes

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> Thymus involutes

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> MSCs & functional fibroblasts

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -black-> Macular Degeneration

Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues. -green-> Immune System & Apoptosis kill some cancer cells

Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction -black-> neocortex neurons & synapses

Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction -black-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction -black-> Neuroendocrine & immune functions degrade

Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction -black-> MSCs & functional fibroblasts

AGE signaling changes MSC Diffn -black-> MSCs & functional fibroblasts

AGE signaling changes MSC Diffn -black-> Osteoblasts

Healthy endocrine cells -black-> Neuroendocrine & immune functions degrade

Healthy endocrine cells -black-> Good Hormone Levels

neocortex neurons & synapses -black-> Alzheimerʼs & related Dementias

Commanding neuroendocrine cells in hypothalamus -black-> Neuroendocrine & immune functions degrade

neurons in SN -black-> Parkinsonʼs Disease

Apop of articular chondrocytes -black-> Articlular cartilage deteriorates

Fibroblasts & MSCs repair ECM -pink-> brown

Fibroblasts & MSCs repair ECM -pink-> Damaged, crosslinked, glycated, oxidized ECM proteins accumulate & change EC environment

Neurotoxins destroy neurites, synapses & neurons -red-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

Neurotoxins destroy neurites, synapses & neurons -red-> Sick Cells: Accumulated cytoplasmic damage causes some cells to function poorly or self-destruction

Neurotoxins destroy neurites, synapses & neurons -black-> Alzheimerʼs & related Dementias

Neurogenesis by Adult Neural Stem Cells -green-> neocortex neurons & synapses

Neurogenesis by Adult Neural Stem Cells -green-> Motor neurons

Neurogenesis by Adult Neural Stem Cells -green-> Commanding neuroendocrine cells in hypothalamus

Neurogenesis by Adult Neural Stem Cells -green-> neurons in SN

BDNF preserves neurons & improves synapses -purple-> neocortex neurons & synapses

BDNF preserves neurons & improves synapses -purple-> Motor neurons

BDNF preserves neurons & improves synapses -purple-> Commanding neuroendocrine cells in hypothalamus

BDNF preserves neurons & improves synapses -purple-> neurons in SN

Macrophages bid to AGE-collagen -black-> Macrophages ingest peroxidized Lipidsm LDL, & RBCs to become Foam Cells

Macrophages bid to AGE-collagen -black-> Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6.

Macrophages ingest peroxidized Lipidsm LDL, & RBCs to become Foam Cells -black-> Atherosclerotic plaque buildup

Cell detachment promotes metasis -black-> Cancer

Endothelium extravasates small clots & debris in capillaries -black-> Small clots in neural capillaries cause micro-strokes

Stimulate Fibroblast & MSC repair of ECM -green-> Fibroblasts & MSCs repair ECM

Toxic heavy Metals Pb, Hg, Pesticides -red-> Neurotoxins destroy neurites, synapses & neurons

Exercise or Hormone Therapy -purple-> Good Hormone Levels

Exercise or Hormone Therapy -purple-> Neurogenesis by Adult Neural Stem Cells

Exercise or Hormone Therapy -purple-> BDNF preserves neurons & improves synapses

Exercise or Hormone Therapy -purple-> Thymus involutes

Exercise or Hormone Therapy -purple-> Neuroendocrine & immune functions degrade

Fasting or CR or Drugs that mimic fasting -green-> Fasting, CR or Exercise reduce LDL levels

Fasting or CR or Drugs that mimic fasting -green-> Glucose Concentration in Bloodstream. (Moderate in healthy people; higher in Diabetes)

Fasting or CR or Drugs that mimic fasting -green-> ROS generated by mitochondrial metabolism

Fasting or CR or Drugs that mimic fasting -green-> Autophagosome assembles. Engulfs damaged Lysms. Transports to new Lysm.

Fasting or CR or Drugs that mimic fasting -green-> LON Protease mRNA

Fasting or CR or Drugs that mimic fasting -green-> Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6.

Fasting or CR or Drugs that mimic fasting -green-> Acetylation of Histones

Fasting or CR or Drugs that mimic fasting -purple-> Neuroendocrine & immune functions degrade

Meditation -purple-> Neuroendocrine & immune functions degrade

Anti-Inflammatory Foods & Drugs -green-> Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6.

Psychological Stress -purple-> Neuroendocrine & immune functions degrade

Pathogenic Infectious Agents, viruses, bacteria, microbes -red-> Pathogenic Infections kill cells & generate inflammation

Persistent, asymptomatic Infections, eg. CMV, occupy immune system -black-> Anergic T-cell clones accumulate & suppress naive T-cells

Macular Degeneration -black-> Blindness

Pathogenic Infections kill cells & generate inflammation -red-> Cell Death: Apoptosis & necrosis kill important cells in slowly renewing tissues.

Pathogenic Infections kill cells & generate inflammation -red-> Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6.

Osteoporosis -black-> Weakness, Frailty

Sarcopenia -black-> Weakness, Frailty

Neuroendocrine & immune functions degrade -purple-> Menopause

Neuroendocrine & immune functions degrade -purple-> Cell-to-cell Signaling pathways

Neuroendocrine & immune functions degrade -purple-> Good Hormone Levels

Neuroendocrine & immune functions degrade -purple-> Many other downstream effects of AGING

Neuroendocrine & immune functions degrade -black-> Osteoporosis

Neuroendocrine & immune functions degrade -black-> Pathogenic Infections kill cells & generate inflammation

Neuroendocrine & immune functions degrade -black-> Impaired wound healing & tissue repair

Neuroendocrine & immune functions degrade -red-> Immune System & Apoptosis kill some cancer cells

Working memory & exec function decline -black-> Alzheimerʼs & related Dementias

Alzheimerʼs & related Dementias -black-> Working memory & exec function decline

Retinopathy -black-> Blindness

Stiff arteries & capilaries, systolic hypertension, cardiovascular disease -black-> Hemorrhagic Stroke

Stiff arteries & capilaries, systolic hypertension, cardiovascular disease -black-> Ischemic Stroke

Stiff arteries & capilaries, systolic hypertension, cardiovascular disease -black-> Heart Failure

Stiff arteries & capilaries, systolic hypertension, cardiovascular disease -black-> Retinopathy

Stiff arteries & capilaries, systolic hypertension, cardiovascular disease -black-> Alzheimerʼs & related Dementias

Atherosclerotic plaque buildup -black-> Ischemic Stroke

Atherosclerotic plaque buildup -black-> Heart Failure

Atherosclerotic plaque buildup -black-> Heart Attack

Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6. -red-> Atherosclerotic plaque buildup

Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6. -red-> Many other downstream effects of AGING

Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6. -red-> Cancer

Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6. -red-> Rheumatoid Arthritis

Inflammation, tissue remodeling, Inflammatory proteins secreted by Liver: C-RP, IL-6. -red-> Oxidation & cleavage of ECM proteins

Small clots in neural capillaries cause micro-strokes -black-> Ischemic Stroke

Lung Alveoli degraded -black-> Pulmonary Emphysema, COPD

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