Ageing and immunology Flashcards
Examples of diseases associated with ageing.
Neurodegenerative disorders
Cardiovascular diseases
CAs
Autoimmune diseases
COVID-19
Intersection of ageing biology and chronic disease
Ageing biology (changes in signalling, epigenome etc) leads to disease and less function -> CA, Neurodegeneration.
What are the three levels of hallmarks of ageing?
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).
What immunological alteration take place in the innate response during immunosenecense?
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!
What immunological alteration take place in the adaptive response during immunosenecense?
AB production and the levels go down.
Naive memory cells exhausted.
Inflammaging
Stimuli to NFkB -> increased production of inflammatory cytokines.
This leads to:
Impaired autophagy
Changes in proteostasis
Mitochondrial dysfunction
Microbiota dysbiosis
Cell senescence
T cells during immunosenescence
Naive T cell decreases
Memory T cell increases
TCR diversity decreases
Effector T cell decreases
Virtual memory cell increases
AG recognition decreases
NK cells during immunosenescence
Cytokine production decreases
CD56 dim and NKG2C increases.
Dendritic cells during immunosenescence
Everything drops (AG presentation, endocytosis, IFN production)
Macrophages during immunosenescence
Everything decreases (number and function, AG presentation, phagocytosis)
B cells during immunosenescence
Naive decrease
Memory increase
MDSCs during immunosenescence
Stands for myeloid derived suppressor cell - number and function increases.
Efferocytosis
Efferocytosis is the effective clearance of apoptotic cells by professional and non-professional phagocytes.
Macrophage efferocytosis
Apoptosis -> recognition and clearing -> macrophage secretion of pro-resolution CKs
Macrophage impaired efferocytosis
Necrosis - release of histotoxic neutrophil contents -> macrophage secretes pro-inflammatory CKs.
Age related changes to macrophages during MSK repair and CA.
Become impaired and altered -> pro-inflammatory
The transition to reparative macrophages is altered?
SASP
Senescence-Associated Secretory Phenotype
It can be transient (beneficial) or persistent (detrimental).
Over time becomes persistent.
What are transients SASPs?
Anti-fibrotic
Anti-inflammatory
SC clearance
Tissue Patterning
What are persistent SASPs?
Pro-fibrotic
Pro-inflammatory
SC accumulation
Stem Cell Exhaustion
Tissue dysfunction
What is the scale of SASP?
Development - repair - regeneration - tumour suppression - tumour progression - chronic inflammation - age-related diseases
What are the effects of SASPs on the microenvironment?
Matrix remodelling
Mitogenic Signals
Clearance regulation
Inflammation
Immune modulation
Cell proliferation
Cell migration
Cell differentiation
Cell plasticity
Vascularisation
Examples of SASP related age-related diseases?
They accumulate and arrest proliferation:
NAFLD
T2DM
OA,OP
BPH
Presbycusis
Age-related macular degeneration
PD, AD
COPD
HF
Senescence
Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome
Senescence leads to
Metabolic changes (lysosomal and mitochondrial expansion)
Reinforcement of growth arrest
Resistance to apoptosis
Autophagy (increased early, decreased late)
Assessing senescence in vitro and in vivo
Cell surface markers
Chromatin reorganisation
Cell cycle arrest
Metabolic adaptations
Morphological changes
Lysosomal compartment
Secretory phenotype
How is altered redox balance accelerates ageing?
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.
Thymus in ageing
Thymus - involution (decreased output of mature T cells)
Bone marrow in ageing
Decreased B cell maturation. Impaired haematopoiesis due to increased adiposity of bone marrow.
Spleen and lymph nodes in ageing
Reduced number and size of follicles.
Decreased CXCL 13 expression in follicles.
Reduced B cell migration into follicles.
Lungs in ageing
Increased infiltration of pro-inflammatory cells and lung tissue damage.
Changes in T and B cells during immunosenescence
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
Successful aging - elderly
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.
Successful ageing - centenarians
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.
What lifestyle modification slows ageing related diseases?
Physical activity
Calorie restriction
Maintaining optimal nutrition
What pharmacological interventions reduce inflammaging?
Caloric restriction mimics
Reversal of thymic atrophy (IL7 therapy)
Statins
PI3Kinase inhibitors
P38 MAPK inhibition
Vaccination
Adjuvants should work with the ageing immune system.
Innate immune response to vaccination (muscle) in ageing.
Increased haematopoetic stem cell differentiation skewed towards myeloid lineage.
Decreased:
migratory capacity
chemotaxis
phagocytosis
Adaptive immune response to vaccination (lymph node) during ageing.
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
Clinical approaches in immunomodulatory interventions
Checkpoint inhibitors
Anti-PD-L1
MAPK inhibitors (Spermidine)
mTOR inhibitors (Rapamycin)
