Ageing and immunology

Question 1

Examples of diseases associated with ageing.

Answer 1

Neurodegenerative disorders
Cardiovascular diseases
CAs
Autoimmune diseases
COVID-19

Question 2

Intersection of ageing biology and chronic disease

Answer 2

Ageing biology (changes in signalling, epigenome etc) leads to disease and less function -> CA, Neurodegeneration.

Question 3

What are the three levels of hallmarks of ageing?

Answer 3

Systematic level (nutritional dysregulation)

Cellular level (cellular senescence, stem cell exhaustion, altered intracellular signalling)

Molecular level (genomic instability, telomere shortening, epigenetic alteration, loss of proteostasis, compromised autophagy, mitochondrial dysfucntion).

Question 4

What immunological alteration take place in the innate response during immunosenecense?

Answer 4

DC decreases the expression of CD80, MHC II and IFN-I

Neutrophils decrease their activity - reduced phagocytosis.

NK cells produce less IFN-gamma.

Inflammatory CK production goes up!

Question 5

What immunological alteration take place in the adaptive response during immunosenecense?

Answer 5

AB production and the levels go down.

Naive memory cells exhausted.

Question 6

Inflammaging

Answer 6

Stimuli to NFkB -> increased production of inflammatory cytokines.

This leads to:
Impaired autophagy
Changes in proteostasis
Mitochondrial dysfunction
Microbiota dysbiosis
Cell senescence

Question 7

T cells during immunosenescence

Answer 7

Naive T cell decreases
Memory T cell increases
TCR diversity decreases
Effector T cell decreases
Virtual memory cell increases
AG recognition decreases

Question 8

NK cells during immunosenescence

Answer 8

Cytokine production decreases
CD56 dim and NKG2C increases.

Question 9

Dendritic cells during immunosenescence

Answer 9

Everything drops (AG presentation, endocytosis, IFN production)

Question 10

Macrophages during immunosenescence

Answer 10

Everything decreases (number and function, AG presentation, phagocytosis)

Question 11

B cells during immunosenescence

Answer 11

Naive decrease
Memory increase

Question 12

MDSCs during immunosenescence

Answer 12

Stands for myeloid derived suppressor cell - number and function increases.

Question 13

Efferocytosis

Answer 13

Efferocytosis is the effective clearance of apoptotic cells by professional and non-professional phagocytes.

Question 14

Macrophage efferocytosis

Answer 14

Apoptosis -> recognition and clearing -> macrophage secretion of pro-resolution CKs

Question 15

Macrophage impaired efferocytosis

Answer 15

Necrosis - release of histotoxic neutrophil contents -> macrophage secretes pro-inflammatory CKs.

Question 16

Age related changes to macrophages during MSK repair and CA.

Answer 16

Become impaired and altered -> pro-inflammatory

The transition to reparative macrophages is altered?

Question 17

SASP

Answer 17

Senescence-Associated Secretory Phenotype

It can be transient (beneficial) or persistent (detrimental).

Over time becomes persistent.

Question 18

What are transients SASPs?

Answer 18

Anti-fibrotic
Anti-inflammatory
SC clearance
Tissue Patterning

Question 19

What are persistent SASPs?

Answer 19

Pro-fibrotic
Pro-inflammatory
SC accumulation
Stem Cell Exhaustion
Tissue dysfunction

Question 20

What is the scale of SASP?

Answer 20

Development - repair - regeneration - tumour suppression - tumour progression - chronic inflammation - age-related diseases

Question 21

What are the effects of SASPs on the microenvironment?

Answer 21

Matrix remodelling
Mitogenic Signals
Clearance regulation
Inflammation
Immune modulation
Cell proliferation
Cell migration
Cell differentiation
Cell plasticity
Vascularisation

Question 22

Examples of SASP related age-related diseases?

Answer 22

They accumulate and arrest proliferation:

NAFLD
T2DM
OA,OP
BPH
Presbycusis
Age-related macular degeneration
PD, AD
COPD
HF

Question 23

Senescence

Answer 23

Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome

Question 24

Senescence leads to

Answer 24

Metabolic changes (lysosomal and mitochondrial expansion)

Reinforcement of growth arrest

Resistance to apoptosis

Autophagy (increased early, decreased late)

Question 25

Assessing senescence in vitro and in vivo

Answer 25

Cell surface markers Chromatin reorganisation Cell cycle arrest Metabolic adaptations Morphological changes Lysosomal compartment Secretory phenotype

Question 26

How is altered redox balance accelerates ageing?

Answer 26

Inflammatory condition favour redox state (NOX, TNF-alpha, IL-1B, COX, XO, MPO). Leads to increased oxidative stress, tissue damage which results in increased ROS and decreased antioxidants -> chronic inflammation.

Question 27

Thymus in ageing

Answer 27

Thymus - involution (decreased output of mature T cells)

Question 28

Bone marrow in ageing

Answer 28

Decreased B cell maturation. Impaired haematopoiesis due to increased adiposity of bone marrow.

Question 29

Spleen and lymph nodes in ageing

Answer 29

Reduced number and size of follicles. Decreased CXCL 13 expression in follicles. Reduced B cell migration into follicles.

Question 30

Lungs in ageing

Answer 30

Increased infiltration of pro-inflammatory cells and lung tissue damage.

Question 31

Changes in T and B cells during immunosenescence

Answer 31

Decrease: Naive lymphocyte production Lymphocyte repertoire diversity Effector cell functionality Lymphocyte proliferation Post-vaccination AB titers Increase: Terminally-differentiated memory lymphocytes Dysregulated CK production Lymph node fibrosis Susceptibility to infectious disease

Question 32

Successful aging - elderly

Answer 32

Elderly: increased subtypes from naive to exhausted, cytotoxic and regulatory T cells. Decrease in proliferation ability and cytotoxicity of CD8 T cells Decrease in naive B cells and high-affinity AB. NK: decreased CD56 bright immunoregulatory cells Increased CD56dim cytotoxic cells Decreases neutrophil phagocytic ability, adhesion and chemotaxis Increased inflammatory molecules. Susceptible to age-related diseases.

Question 33

Successful ageing - centenarians

Answer 33

Expansion of cytotoxic cells Highly differentiated CD8 + Decrease in the number of B cells (Increase in naive B cells and IgM) Increased cytotoxic capacity of NK cells Increased IFN-gamma prod. Increased neutrophil chemotaxis and microbicidal capacity. Decrease in neutrophil adherence. Increased anti-inflammatory molecules. Avoid or delay susceptibility to age-related diseases.

Question 34

What lifestyle modification slows ageing related diseases?

Answer 34

Physical activity Calorie restriction Maintaining optimal nutrition

Question 35

What pharmacological interventions reduce inflammaging?

Answer 35

Caloric restriction mimics Reversal of thymic atrophy (IL7 therapy) Statins PI3Kinase inhibitors P38 MAPK inhibition

Question 36

Vaccination

Answer 36

Adjuvants should work with the ageing immune system.

Question 37

Innate immune response to vaccination (muscle) in ageing.

Answer 37

Increased haematopoetic stem cell differentiation skewed towards myeloid lineage. Decreased: migratory capacity chemotaxis phagocytosis

Question 38

Adaptive immune response to vaccination (lymph node) during ageing.

Answer 38

Increased: pre-existing memory T and B cells Exhausted T cells and pro-inflammatory B cells Decreased: T and B cell repertoire diversity Naive T and B cell pool New memory cell formation AB quality, quantity and durability

Question 39

Clinical approaches in immunomodulatory interventions

Answer 39

Checkpoint inhibitors Anti-PD-L1 MAPK inhibitors (Spermidine) mTOR inhibitors (Rapamycin)