Splicing and age related diseases more generally (LLM response - chatGPT)

Prompt: ""of the diseases of aging which are assocated with changes to RNA splicing"

Diseases of Aging Associated with Changes to RNA Splicing

Many major age-related diseases have documented links to altered RNA splicing—both via age-related drift in the spliceosome and via disease-specific mutations in splicing factors or cis-elements. Below are key examples by system (not exhaustive, but covering major, well-supported cases).

1. Neurodegenerative Diseases

Alzheimer’s disease (AD)

• What’s altered?
  • Alternative splicing of tau (MAPT), shifting 3R/4R isoform balance.
  • Splicing of APP, PSEN2, and various synaptic genes.
• Mechanism: Mis-spliced tau isoforms are more aggregation-prone and disturb microtubules; age-related decline in spliceosome components (e.g. SRSF and hnRNP proteins) pushes splicing patterns in a pro-pathology direction.

Frontotemporal dementia (FTD) and other tauopathies

• What’s altered?
  • MAPT exon 10 splicing mutations cause familial FTD with parkinsonism (FTDP-17), directly changing the 3R/4R tau ratio.
• Mechanism: Mutations in intronic/exonic splicing enhancers and silencers around exon 10 skew splicing. This is a clear example where a single splicing defect can cause late-onset neurodegenerative tauopathy.

Parkinson’s disease (PD)

• What’s altered?
  • Alternative splicing of α-synuclein (SNCA), LRRK2, and numerous synaptic/mitochondrial genes.
• Mechanism: Some SNCA splice variants are more aggregation-prone or differently localized; spliceosome dysfunction and splicing-factor changes are increasingly observed in PD tissue.

Amyotrophic lateral sclerosis (ALS) / FTD (TDP-43, FUS, etc.)

• What’s altered?
  • Nuclear RNA-binding proteins TDP-43 (TARDBP) and FUS regulate splicing; their mislocalization and aggregation lead to widespread mis-splicing in aging motor neurons and cortex.
• Mechanism: Loss of nuclear TDP-43 causes cryptic exon inclusion and abnormal splicing in dozens–hundreds of neuronal genes (e.g. STMN2), damaging axonal maintenance and synapses.

2. Cancers (Solid and Hematologic)

Virtually all cancers become more common with age, and splicing changes are now considered a major feature of many malignancies.

Hematologic malignancies (MDS, AML, CLL, etc.)

• What’s altered?
  • Recurrent somatic mutations in core splicing factors: SF3B1, SRSF2, U2AF1, ZRSR2, among others.
• Mechanism: These mutations skew 3′ splice-site choice or exon inclusion/exclusion in a large gene set (DNA repair, epigenetic regulators, cytokine signaling), promoting clonal expansion and transformation—especially in older bone marrow.
• Example: SF3B1-mutant myelodysplastic syndrome (MDS) is strongly age-associated and defined by characteristic aberrant splicing signatures.

Solid tumors (breast, lung, colon, prostate, etc.)

• What’s altered?
  • Cancer-specific splice isoforms of oncogenes and tumor suppressors, such as BCL-X (BCL2L1), CD44, PKM (PKM2), Mdm2, and VEGF.
• Mechanism:
  • Pro-survival vs pro-apoptotic isoforms (e.g. BCL-XL vs BCL-XS).
  • Metabolic isoform switching (PKM2 over PKM1) favoring aerobic glycolysis.
  • Enhanced motility and invasion via CD44 variant exons.
  Age favors accumulation of mutations and epigenetic changes in splice sites/regulatory elements and in splicing-factor genes themselves.

3. Cardiovascular and Metabolic Disease

Cardiomyopathies / Heart Failure

• What’s altered?
  • Splicing of titin (TTN) isoforms (N2B vs N2BA).
  • Splicing changes in myosin-binding protein C, ion channels, and Ca²⁺-handling proteins.
• Mechanism: Age- or stress-driven splicing shifts change passive stiffness and contractility. Fetal splicing programs can be re-activated in failing aged hearts.

Atherosclerosis and Vascular Aging

• What’s altered?
  • Alternative splicing in vascular smooth muscle contractile proteins (MYH11, ACTA2), inflammatory mediators, and adhesion molecules.
• Mechanism: Splicing changes shift smooth muscle from a contractile to a synthetic/pro-inflammatory phenotype and alter endothelial responses to shear stress; these changes accumulate with age and metabolic stress.

Type 2 Diabetes and Insulin Resistance

• What’s altered?
  • Splicing variants in insulin receptor (INSR) (A vs B isoforms), PPARG, LRP1, and numerous metabolic regulators.
• Mechanism: The INSR-A/INSR-B ratio affects insulin signaling; age-related and obesity-related splicing changes in adipose, liver, and muscle contribute to insulin resistance.

4. Musculoskeletal Aging

Sarcopenia (Age-related Muscle Loss)

• What’s altered?
  • Alternative splicing of troponin T (TNNT3), titin, ryanodine receptor (RYR1), and other excitation–contraction coupling genes.
• Mechanism: Age-related shifts from adult to more “embryonic” or dysfunctional isoforms impair force generation and Ca²⁺ handling in muscle fibers.

Osteoarthritis

• What’s altered?
  • Splicing of cartilage matrix genes (e.g. COL2A1, aggrecan) and inflammatory mediators.
• Mechanism: Some splice variants promote matrix breakdown or reduce repair capacity in aged chondrocytes, amplifying mechanical damage.

5. Immune Aging (Immunosenescence) and Autoimmunity

Immunosenescence & “Inflammaging”

• What’s altered?
  • Broad splicing changes in T-cell receptor signaling components, co-stimulatory molecules, cytokine receptors, and transcription factors in aged T and B cells.
• Mechanism: Mis-splicing contributes to skewing toward memory/effector phenotypes, reduced naive repertoire, and chronic low-grade inflammation characteristic of older adults.

Age-associated Autoimmunity (e.g. Late-onset SLE, RA)

• What’s altered?
  • Alternative splicing of CD45 (PTPRC) in T cells is a classic example; mis-splicing has been linked to breakdown of tolerance and susceptibility to autoimmunity.
• Mechanism: Different CD45 isoforms tune T-cell receptor signaling thresholds; age-related shifts can make T cells hyper- or hypo-responsive.

6. Progeroid and Premature Aging Syndromes

These are rare but mechanistically clean links between splicing/processing machinery and an aging phenotype.

Hutchinson–Gilford Progeria (HGPS)

• What’s altered?
  • A silent mutation in LMNA activates a cryptic splice site, producing progerin, a truncated lamin A isoform.
• Mechanism: Progerin accumulation causes nuclear envelope defects, DNA damage, and systemic premature aging with classic late-life pathologies (atherosclerosis, bone loss, etc.).

Werner Syndrome and Other DNA-repair Progerias

• Splicing defects have been reported in some patients’ WRN and related genes. The core issue is usually DNA helicase function, but mis-splicing can exacerbate the phenotype and contribute to accelerated aging features.

7. Eye and Sensory Aging

Age-related Macular Degeneration (AMD)

• What’s altered?
  • Alternative splicing of VEGF, CFH, and other complement/angiogenesis genes in the retina and choroid.
• Mechanism: Pathogenic VEGF splice isoforms favor neovascularization and leakage; complement splicing changes can amplify chronic inflammation in the aging retina.

Presbycusis (Age-related Hearing Loss)

• What’s altered?
  • Splicing of ion channels and structural proteins in the cochlea; less well characterized but emerging as an area of interest.

8. “Pure” Splicing Diseases that Present as Age-related Worsening

Some classical spliceopathies are genetic but show progressive worsening with age, so they often look like exaggerated aging of a particular tissue:

• Myotonic dystrophy type 1/2 – toxic CUG/CCUG repeats sequester MBNL, causing fetal-to-adult splicing reversion in muscle, heart, and brain. This produces insulin resistance, cataracts, and arrhythmias, which resemble accelerated aging of those systems.
• Spinal muscular atrophy (SMA) – SMN2 exon 7 skipping; more childhood-onset but mechanistically a clear splice-switch disease.

Big-picture Take-home

• Age itself changes splicing: Expression, phosphorylation, and localization of splicing factors (SR proteins, hnRNPs, core spliceosomal subunits) shift with age in many tissues, leading to a characteristic “aging splicing signature”.
• Many major diseases of aging—neurodegeneration, cancer, cardiovascular and metabolic disease, sarcopenia, osteoarthritis, AMD, and immunosenescence—either:
  • are driven directly by mutations in splicing machinery/targets, or
  • are strongly modulated by age-driven splicing drift.