Senescent Cells in

The Development of
Cardiometabolic Disease

Andrea C. Postmus, Ines Sturmlechner, Johan W. Jonker,

Jan M. van Deursen, Bart van de Sluis, and Janine K. Kruit
 INTRODUCTION
Senescence (1961) by Hayflick
Cellular senescence : telomere
and Moorhead  fibroblasts in
shortening, oncogenic activity
culture were only able to divide
and stressors (DNA damage,
a limited number of times
oxidative stress, inflammatory
before entering a state of
mediators and metabolites)
permanen growth arrest

Proinflammatory cytokines, chemokines, growth factors and

proteases  senescence associated secretory phenotype (SASP)
 Key Points
Senescent cells contribute to adipose tissue dysfunction
leading to systemic metabolic alterations

Adipose dysfunction leads to accelerated accumulation of

senescent cells in other tissues

Senescent cells contribute to the development and progression

of NAFLD

Selective elimination of senescent cells in an atherosclerotic-

prone mouse model results in decreased lesion formation and
increased plaque stability
 Senescence as inducer of
adipose tissue dysfunction
AGEING Distribution And Function Of
Adipose Tissue Changes
OLD AGE

DIMINISHED LIPID Reduction In (Swat)

HANDLING, ALTERED And (BAT) +
SECRETION OF Increased Of Visceral
ADIPOKINES, LOW- WAT (Vwat)
GRADE
INFLAMMATION,
DEFECTIVE Insulin Resistance And
ADIPOGENESIS Dyslipidaemia
 Senescence as inducer of
adipose tissue dysfunction
Reduction of the Pro-
Removal of Senescent
Inflammatory SASP Factor
Cells in Mice
Interleukin 6 (IL-6)

Excessive calorie intake Senescent cell

and genomic instability accumulation!!!

Senescent cell accumulation in

Obesity and Diabetes
adipose tissue  adipose
(HUMAN)
tissue dysfunction
 Senescence as inducer of
adipose tissue dysfunction
• Critical role for endothelial PPARg in adipose tissue
expansion in response to a high fat diet deletion of
PPARg  reduced adipose tissue mass and adipocyte size

• Cellular senescence (adipose tissue endothelial cells)

impairing fatty acid handling and enhancing immune cell
infiltration

• Visceral adipose tissue (obese individuals)  enhanced

expression of pro-inflammatory mediators and senescence
markers
 Senescence as inducer of
adipose tissue dysfunction
• Senescent cells (adipose tissue during ageing, obesity and
diabetes)  disrupt the adipose tissue microenvironment
(via secretion of SASP components) adipose tissue
inflammation and insulin resistance

• Adverse systemic effects of senescent adipose tissue cells

were revealed via transplantation experiments of senescent
adipocyte progenitors into fat tissue of healthy young mice
Role of senescence in
nonalcoholic fatty liver disease
NAFLD  accumulation of excess fat within hepatocytes
(steatosis). Relatively benign  25% into nonalcoholic
steatohepatitis (NASH)  fibrosis, cirrhosis and hepatocellular
carcinoma (HCC)

Excessive calorie intake  upregulation of senescence markers

in hepatocytes  lipid deposition in the liver  restriction and
exercise (ameliorated)

Induction of senescence (isolated primary hepatocytes) 

mitochondrial dysfunction  reduced fatty acid oxidation
capacity  steatosis
 Role of senescence in
nonalcoholic fatty liver disease
NAFLD to NASH  activation of innate immune cells  hepatic
inflammation  by secretion of SASP factors (Senescent cells)

NAFLD  increased expression of STING in nonparenchymal

liver cells  liver steatosis and inflammation

Studies suggest that senescent cells

in the liver may contribute to the
progression of NAFLD
Role of cellular senescence in
atherosclerosis
Ageing  proatherogenic (vasculature) 
arterial stiffness, calcification, increased arterial permeability

Dyslipidaemia 
initiates and accelerates atherosclerotic plaque formation

Vascular smooth muscle cells (VSMCs) and vascular

endothelial cells  human atherosclerotic plaques 
features of senescence
Role of cellular senescence in
atherosclerosis
VSMC senescence 
atherosclerosis development and plaque vulnerability

Senescent cells  pro-inflammatory SASP cytokines macrophage

influx + matrix-degrading  plaque formation and vulnerability

Role of VSMC senescence in atherosclerotic plaque 

accumulation of foamy macrophages might be detrimental for
lesion progression and stability
 CONCLUSION
CELLULAR ADIPOSE LOW GRADE INFLAMATION AND
SENESCENCE DYSFUNCTION INHIBIOTN ADIPOGENIC
DIFFERENTIATON

INSULIN RESISTANCE
DYSLIPIDAEMIA
CARDIOMETABOLIC

TREATMENT OR PREVENTION OF
REMOVAL OF SENESCENT CELLS
THESE DISEASES

SENOLYTIC AGENT!!!
THANK YOU
VERY MUCH