Discussion

Question 1

What does current literature say about VSMCs in cSVD?

Answer 1

My finding that senescence is lower in cSVD than age matched controls doesn’t contradict current literature as that states VSMCs are:

• damaged (?BBB incompetency)
• lost (Pantoni, 2010)
• degenerate (Lammie, 2002)
• replaced by colagens & laminin (Lammie, 2002)

Vessel wall remodelling - hypothesised as an adaptive response to HTN but ultimately maladaptive as it causes loss of reactivity & autoregulation - stroke, bleeds, white matter lesions

Question 2

If not senescence then what (3 answers)?

Answer 2

• apoptosis
• de-differentiation (shift from contractile to secretory phenotype)
• different type of senescence e.g AKT & knockdown ot PTEN pathway

But this is all SPECTULATION

Question 3

What supports a hypothesis of apoptosis in cSVD VSMCs?

Answer 3

• hereditary cSVD (CADASIL study suggested VSMC apoptosis - similar changes to sporadic cSVD but more rapid & agrressive)
• oxidative stress suggested to cause VSMC apoptosis (may be associated with pathogenesis or risk factors)
• atheroscelorsis, a large vessel disease, exhibits VSMC apoptosis in plaque rupture & vessel remodelling (similar risk factors, loss of VSMCs & stenotic resulting vessels)

Question 4

How are ROS generated in cerebral arterioles?

Answer 4

• Enzymes e.g. NADPH oxidases which generate hydrogen peroxide
• Disruption of balance of oxidants to anti-oxidants may cause stress

Question 5

What is the significance of surviving non-senescent VSMCs in cSVD?

Answer 5

May reflect:

• incomplete pathology
• early stage disease
• patchy and diffuse change

-or resilience!

Question 6

Is there any contradictory evidence against your study?

Answer 6

Senescence has previously been linked to ageing vasculature & age-related organ dysfunction, hence the original hypothesis.

Two specific examples include:
1) Atherosclerosis: senescent VSMCs & endothelial cells as well as histone modifications have been demonstrated on histoology - thought to contribute to atherogenesis

2) Endothelial senescence (and perhaps more tenuously VSMC senescence) is linked to age-related BBB dysfunction - BBB dysunction being an increasingly popular theory of causality for cSVD - all very unclear at present

Question 7

Is senescence associated with VASCULAR ageing?

Answer 7

-YES senescnece of endothelial & vascular cells (Kida and Goligorsky, 2016)

Question 8

Is senescence always deleterious?

Answer 8

• NO in early life it is considered beneficial as it in an anti-cancer mechanism, however in later life it is generally considered deleterious
• This fits with the antagonistic pleiotropic theory of genes (naturally selected for)

Question 9

What are the proposed mechanisms linking senescence to ageing?

Answer 9

1) SASP damaging tissue structure and function
2) suppression of stem cell proliferation is thought to impair tissue regeneration
3) impaired response to oxidative stress
4) calcification and dysfunction

Question 10

What are the components of the SASP?

Answer 10

• Chemokines
• interleukins e.g. 6
• ICAM-1
• upregulation of innate immune receptors e.g. TLR4
• MMPs

Question 11

Could delayed cell senescence cause resilience against an ageing vascular phenotype?

Answer 11

• Yes… evidence comes from SIRT gene & sirtuin1 protein - function in humans not fully determined
• SIRT is protective against oxidative stress & against premature VSMC senescence

Question 12

Is there a correlation between VSMC senescence & age?

Answer 12

-Literature is suggestive, however in this study perhaps due to small cohort and small age range (80-96yrs) we did not find one