TABLE 1

Evidence for ageing hallmarks in chronic obstructive pulmonary disease (COPD)

Hallmark	Marker	*COPD versus* non-COPD**	COPD cell origin	CSE-treated cells	References
Genomic instability	γ-H2A.X	↑	Lung tissue sections, AT1, AT2, HBEC and PV-EC	HBEC, HFL1 and MRC-5	[75, 76, 78, 79]
	Ku70	↓	Peripheral leukocytes		[80]
	Ku80	↓	Lung homogenates		[77]
Telomere shortening	Length	↓	Lung homogenates AT2, PA-SMC, PV-EC and peripheral leukocytes	SAEC (COPD) and HFL1	[78, 81–86]
	Telomerase	↓	PV-EC		[84]
	TPP1	↓	Lung homogenates	SAEC and HFL1	[78]
Epigenetic changes	HDAC activity	↓	Lung homogenates and bronchial biopsies		[92]
Epigenetic changes	SIRT1 and -6	↓	Lung homogenates		[94, 95]
Loss of proteostasis	Autophagy	↑	HBEC	SAEC	[100]
	Autophagy	↓		HBEC (COPD)	[100]
	Autophagosomes	↑	Lung homogenates	HBEC and BEAS-2B	[79, 99, 100]
	Ubiquitin	↑	Lung homogenates		[98, 100]
	p62	↑	Lung homogenates		[79, 100]
Deregulated nutrient sensing	S6K (mTOR)	↑^#	Lung homogenates and peripheral leukocytes	HBEC	[79, 103]
Deregulated nutrient sensing	IGF1	↑	SAEC		[104]
Mitochrondrial dysfunction	ROS	↑		HBEC, BEAS-2B and MRC-5	[76, 108, 109]
	Oxidised DNA	↑	Lung homogenates		[77]
	Lipid peroxidation	↑	Lung homogenates		[105, 106]
	Nitric oxide	↑	Lung homogenates		[106]
	Mitophagy	↑	Lung homogenates	HBEC and BEAS-2B	[108, 109]
	Antioxidant	↓	Lung homogenates and HBEC		[107]
	Mitochondrial membrane potential	↓		BEAS-2B	[108]
Immune dysregulation	Klotho	↓	Lung homogenates	HBEC	[112]
	NF-κB	↑	Lung homogenates		[113]
	Pro-inflammatory cytokines	↑	Lung homogenates		[113]
Senescence	SA-β-gal	↑	SAEC, PA-SMC, PV-EC and fibroblasts	SAEC (COPD), HBEC, A549, HFL1 and MRC-5	[76, 78, 79, 84–86, 115–117]
	p16	↑	Lung tissue sections, AT1, AT2, PA-SMC, PV-EC and fibroblasts	HFL1	[75, 76, 78, 84–86, 116, 117]
	p21	↑	Lung homogenates, AT2, PA-SMC, PV-EC and peripheral leukocytes	HBEC, A549 and HFL1	[78–80, 84–86, 117]
	IL-6 and IL-8	↑	Lung tissue sections, AT1, AT2, PA-SMC and PV-EC	MRC-5	[75, 76, 84, 85]
ECM dysregulation	ECM proteins	↑	Lung homogenates		[42]
	Elastogenesis genes	↑	Lung homogenates		[125]
	MMP/TIMP dysregulation	↑	Lung homogenates		[123]
Stem cell exhaustion	Circulating progenitor cells	↓^#	Endothelial and haemopoietic progenitor cells		[137, 138]
	Regenerative capacity	↓	Basal progenitor cells		[135]
	Stem cell function	↓	HBEC		[142]
	WNT signalling	↓^#	Lung homogenates, AT2 and SAEC		[144, 147]
	Notch pathway	↓^#	SAEC		[143]

CSE: cigarette smoke extract; AT1: type I alveolar cells; AT2: type II alveolar cells; HBEC: human bronchial epithelial cells; PV-EC: pulmonary vascular endothelial cells; HFL1: fetal lung fibroblasts; MRC-5: fetal lung fibroblasts; TPP1: telomere protection protein 1; PA-SMC: pulmonary artery smooth muscle cells; SAEC: small airway epithelial cells; HDAC: histone deacetylase; SIRT: sirtuin; BEAS-2B: bronchial epithelial cell line (virus); mTOR: mechanistic target of rapamycin; IGF1: insulin-like growth factor 1; ROS: reactive oxygen species; SA-β-gal: senescence-associated-β-galactosidase; IL: interleukin; A549: alveolar basal epithelial cell line (carcinoma); ECM: extracellular matrix; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinase. ^#: mean age was significantly different between COPD and control group; for the other studies, information was not available or mean age was not different between groups.