Aging

Age ⁵: Muscle & Nerve

Muscle
Child
Adult
Aging
Morphology
Sarcopenia
Nerve
NMJs

From Bramwell: Atlas of Clinical Medicine

Children: Muscle Features

Muscle fibers
- Size: Smaller than adult
- Types
  - 1st year: More 2C fibers (Up to 3%)
  - General: Type 2 fibers 5% smaller than type 1
Nuclei
- Larger
Capillaries
- Lower #/Muscle fiber
- 1st 3 years: Many fibers with no adjacent capillary

Adults: Muscle Features

Nuclei
- Small
- Round
Capillaries
- All muscle fibers have adjacent capillary

NORMAL MUSCLE
Age (Years)	Mean fiber Diameter (μM)
Birth	12 to 15
1	18
3	20
6	27
8	35
10	40
12	45
15	50
Adult	50 to 60

Aging (> 65 years): Muscle Changes ^1,¹¹

Comparative Disorders
Disuse
Microgravity

Sarcopenia: Molecular Pathways
- IGF-1/PI3k/Akt/mTOR signalling: Reduced
- FOXO/Atrogen-1/MuRF1 expression: Increased
Muscle Mass
- Reduction: Slowly progressive
Type 2 muscle fibers
- Reduced size
- 2B fibers: Reduced number
- MYH1: Less expression
- Satellite cells: Fewer associated
Mitochondrial
- SDH+ muscle fibers: More frequent
- COX- muscle fibers: More frequent
- Complex I: Reduced activity ²
- mtDNA ³
  - Levels: Reduced
  - More damage: mtDNA deletions, multiple
Nuclei
- Shape: More irregular
- Size: Often increased
- Numbers: Possibly reduced
Strength correlations
- Time Course: Slow reduction
- Muscle mass: Correlates with
  - Bioavailable testosterone levels
  - Muscle fiber size
- Type 2 muscle fiber size
- NOT: Age per se
Iron content: Increased
Satellite cells
- Epigenetic changes: p16Ink4a (CDKN2A)
  - Cyclin- dependent kinase (CDK) inhibitor
  - Tumor suppressor protein
  - Upregulation with age: Produces
    - Irreversible transition of quiescent SCs to pre-senescent SCs
- Telomere shortening & DNA damage
  - Telomere Length: Normal
  - Telomere Function: Disordered
- DNA damage: Phosphorylated histone H2AX (γH2AX) increased
- Signal pathways
  - JAK/STAT3 activators, coactivator & targets: Upregulation
  - p38 mitogen-activated protein kinase (MAPK) pathway
    - Increased activity: May deplete stem cells
  - Notch signaling pathway
    - Notch receptor ligands (Jagged1; Delta-like-1): Reduced
    - Notch inhibitors (Tumor necrosis factor alpha (TNFα): Increased
- Satellite Cell Numbers
  - Depleted
Other tissues
- Capillary density: Possibly reduced
- Extracellular matrix: Increased Collagen I & II, TGF-α
- NMJs: May be abnormal

Increased age (> 85 years): Common features in muscle

Nuclear shapes: Irregular

H&E stain

H&E stain
Muscle fiber size: Varied

Gomori trichrome stain

ATPase ph 4.3 stain
Type 2 fibers small

ATPase ph 4.6 stain
Smallest fibers: 2B; Intermediate stained

Fiber types: Non-random distribution

ATPase ph 9.4 stain

Acid phosphatase stain
Lipofuscin: Punctate sub-sarcolemmal regions

Esterase stain

Internal architecture
Mildly irregular
Pale (Type 2) fibers small

NADH stain

Age: Nerve changes

Development
- Myelination
  - Onset: 18 weeks of gestation
  - Birth: All fibers initially myelinated
  - Thickness: Increases through childhood
    - Absolute thickness
    - Relative to axon size
  - Internodal length
    - Birth: 200–300 μm
    - Adult: 200 to 1,800 μm
    - Increases in parallel with somatic growth
- Axons
  - Number: Full at birth
  - Density: Reduced with increasing age
  - Diameter: Increases up to 5 years
  - Size distribution: Myelinated axons
    - Birth: Unimodal
    - Adult: Bimodal
  - Conduction velocity
- Endoneurial area: Increases with age
Full maturity: 10 years
Aging
- Axons
  - Myelinated fiber densities: Decrease continuously through adult life
    - By ~50% from 2nd to 8th decade
  - Regeneration
    - Regenerated axons: May become up to 25%
    - Regenerating clusters: More frequent with increased age
  - Conduction velocity
  - Axonal transport: Slowed ⁴
- Myelin & Schwann cells
  - Denervated Schwann cells: Increase with age
  - Myelin thickness & internode length: Increased scatter with age
  - Pi granules: May be increased numbers in older patients
- Endoneurium
  - Endoneurial area & Collagen: Increase with age
  - Endoneurial nuclei: Stable number with age
  - Endoneurial capillaries: Age changes
    - Hyalinization: Increased
    - Endothelial & Pericytic basement membrane: More duplication
- Perineurial basement membrane
  - Increased thickness with age: Most at outer layers