Lecture 9: cellular aging, reprogramming, and rejuvenation

Hallmarks of cellular aging

altered intercellular communication, stem cell exhaustion, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, loss of proteostasis, epigenetic instability, telomere attrition, epigenetic alterations

4 layers of ageing

decline in physical function, alterations in how cells perceive the external world (metabolic and nutrient sensing, alters ability and homeostasis of cells), intracellular workings, molecular level (DNA, proteins, histones, etc.)

central role of ageing in chronic disease

frailty, osteoporosis, diabetes mellitus, dementia, renal failure, vascular disease, macular degeneration, cancer, sarcopenia, neurodegeneration, arthritis, stroke

How do you know if a cell is aged or not?

epigenetic markers, senescence markers, shortage of telomeres

cellular senescence

arrest of cell cycle due to accumulation of stress: start secreting new different stuff, there are a bunch of biomarkers: beta-galactosidase staining, phospho-histone, HP1 IHC, Lamin B1 IF

alterations in cell migration with ageing

the cell “engine” or mechanical properties don’t move as well, must make contact w/ substrate to move, ability to remodel cytoskeleton is reduced, ability to contact cytoplasm has decreased (both of which contribute to the lack of movement)

Heterogeneity in cellular mechanical response with ageing

not a straight line, and can vary across different time periods

ATP production reduces which means the ability to remodel reduces

cells are unable to secrete proper signals

levels of DNA damage

organization of chromatin and cytoskeleton

^^all of these can be measured using things like mass spec, high res imaging, and immuno photosense markers

Transcriptional signatures in ageing

relatively small percentage of an organism’s transcriptome changes with age

a broad group of stress responsive genes increase with age

a variety of genes decrease with age depending on tissue and cell type

splice isoform usage and intron retention change with age

Why do only a small number of gene expressions change with age?

while mechanical properties are changing, the chromatin accessibility isn’t changing too much b/c the nucleus is the most powerful (set up during differentiation)

as cells age, the genome isn’t restructured as much (proven through genome studies)

as we age, these long genes are misregulated more compared to the rest of the genome b/c DNA damage increases and the long genes have the most DNA

transcriptional changes in human skin ageing

single-cell transcriptional landscapes of human skin ageing, dysregulation of cell-type-specific transcriptional networks during skin aging, cell-type-specific downregulation of HES1 or KLF6 accelerates senescence, Quercetin promotes the rejuvenation of aged dermal fibroblasts

What would you focus on if you wanted to revert cell ageing?

epigenetic reprogramming, matrix remodelling

reprogramming

turn on transcription factors —> turn into a stem cell —> deaged

cytoskeleton has to be corrected/remodeled

reset the organization of the genome (by restructuring the genome and reprogramming, the whole cell cleans itself up and starts producing new things), targeting the chromatin