Cellular Aging😊

Cellular Aging

• Main Reasons:
1. Free radical injury (most common)
2. Telomere shortening.
3. Insulin resistance.

Telomere - TAG

• Structure:
• Chromosome ends with TTAGGG tandem repeats at the 3’ end.

• Hayflick Limit:
• Limits cell division due to telomere shortening
• After 50 cell divisions → DNA replication stops → Leads to aging

• Steps
1. On removal of primer from 3’ end
2. The primer nucleotide sequence is not replicated in the daughter strand
3. End replication error
4. Telomere attrition (Shortening of ends of chromosomes)

Telomerase:

Function:

• "Immortality gene"

• RNA dependent DNA polymerase (RDDP).
• Reverse transcriptase activity.
• Mnemonic: Change 6 DP (RDP → RDNA Polymerase) to become immortal

• Contains intrinsic RNA template

• Adds DNA segments to 3’ end
• Prevents telomere shortening
• No Hayflick limit

Expression:

• Absent in somatic cells

• present in
• skin
• hematopoietic
• germline cells
• cancer cells
• lymphocytes

 

Sirtuins:

• Function: Increase sirtuins
• prolong lifespan
• stay young

• Number of Genes: Seven genes.

• Enzyme Activity: 
• Histone deacetylase

• Benefits (ABCD):
• Anti-aging.
• Cancer treatment.
• Diabetes treatment (improves insulin sensitivity).

• How to Increase:
• Red wine consumption.
• Calorie deficit (eat less).

• Mnemonic:
• Sirtuin → God → anti aging, can cure cancer and diabetes
• God can convert water into red wine ()
• He has 7 genies
• But His stone deactivated

Premature Aging (Progeria / Progeroid Syndromes):

• Becoming old very quickly.

Syndrome	Onset	Defect	Other
Werner Syndrome	Adult age	DNA helicase defect.	Adult progeria.
Hutchinson-Gilford Syndrome	Childhood	LMN A gene defect (laminopathy).	e.g., "Paa" movie

• Mnemonic:
• Progeria → progenies → think children
1. some children Go to war (Werner) when adults ()
• in helicopter (helicase)
2. somechildren Hutchi hutchi (Hutchinson) nnu prnj thummi avde irikkum
• they are Lame (Lmna)

• Differentiation: Werner (progeria) vs. Wermer (MEN1 syndrome).

Hutchinson's

• H → Herpes Zoster Ophthalmicus

• U → subUngual Melanoma (superficial spreading melanoma)
• Hutchinson sign

• T → Triad → congenital syphillis
• Peg shaped teeth
• Interstitial Keratitis (IK + SNHL)
• SNHL

• CH → Chauffeur's Fracture/Backfire Fracture
• Intra articular #

• Son → looking older → Hutchison Gilford
• LMN A gene defect (laminopathy).
• Progeria (onset: Child)

• PUPIL → Hutchinson Pupil
• Herniation of uncus (medial temporal lobe) → compresses ipsilateral CN III → same side pupillary dilatation.
• Kernohan’s notch phenomenon:
• False localizing sign
• Ipsilateral pupil dilatation
• Ipsilateral UMN palsy

Free Radical Injuries

• Definition: Also Reactive Oxygen Species (ROS).

• Formation:
• Oxygen → free radicals.
• By: Air/water pollution, poisons, chemicals, toxins.

• Three Main Free Radicals:
1. Superoxide.
2. Hydrogen Peroxide (H2O2).
3. Hydroxyl (OH): 
• Most dangerous/potent.
• Mnemonic: OH → "Oh my god".

• Fenton Reaction: 
• H2O2 → OH (in presence of Fe2+ → Fe3+).
• Mnemonic: Fentin is Fe.

• Pigment formed by Free Radical Injury: 
• Lipofuscin pigment.

Protective Enzymes (Antioxidants):

• Superoxide Dismutase (SOD)
• Converts superoxide → H2O2.
• Which can further be broken down by above enzymes
• metal cofactors
• Mitochondrial SOD : Mn
• Cytoplasmic SOD : Cu

• Glutathione Peroxidase
• Breaks down both H2O2 and OH.

• Catalase
• Breaks down H2O2 → H2O, O2.

SOD1 gene mutation

• Amyotrophic Lateral Sclerosis (ALS) 
• (UMN + LMN disease) → Stephan Hawking

• Other Factors Generating Free Radicals: 
• NADPH oxidase (in phagocytosis)

Respiratory Burst (Oxidative Burst)

• Immune defence mechanism in phagocytes

• Uses O₂ to produce Reactive Oxygen Species (ROS)
• kill pathogens inside phagosomes.

Clinical Pearls

• CGD (Chronic Granulomatous Disease)
• NADPH oxidase deficiency
• DHR > NBT
• Recurrent infections with catalase ⊕ organisms

• Pseudomonas (P. aeruginosa)
• Produces pyocyanin
• generates ROS to kill competitors

• Blue green (diffusible)