Regeneration of the Aging Lung: A Mini-Review

Abstract

Natural lung aging is marked by molecular changes that occur during development, maturation, and late-life decline. At the cellular and whole organ level, degenerative changes that are a hallmark of natural aging (shorter telomeres, increased expression of cellular senescence markers, increased DNA damage, oxidative stress, and apoptosis, accompanied by diminished elasticity) reach pathological levels in aging humans in the form of chronic respiratory disease. Aging strongly correlates with the development and incidence of chronic respiratory diseases, including cancer and idiopathic pulmonary fibrosis, but is most strongly linked with development of chronic obstructive pulmonary disease. Lung failure due to aging can be traced to loss of lung stem cell regenerative capacity within the distinctive stem cell niches found within each compartment of the lung. Current knowledge about the identity and function of these stem cell compartments has been largely drawn from a variety of transgenic and spontaneously mutated mouse models that are characterized by rapid rates of aging or have been used to examine regeneration from injury in the context of natural or accelerated aging. While much work has focused on the failure of epithelial cell populations as a key component of the aging process, additional studies have shown that aging, as a global phenomenon in the lung, also impacts resident endothelial, mesenchymal, and immune cell populations. In this review, we examine aging as a process dependent on specific changes in molecular pathways within multiple lung cell populations.

The aging transcriptome and cellular landscape of the human lung in relation to SARS-CoV-2

“…Whereas epithelial cells decreased with age, fibroblasts increased with age (Figure 3b). This finding is consistent with the progressive loss of lung parenchyma due to reduced regenerative capacity of the aging lung 46 , as well as the increased risk for diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis 47 . In addition, these results are concordant with the findings from analysis of human lung single-cell transcriptomes (Figure 2a-b).…”

Interrupted reprogramming of alveolar type II cells induces progenitor-like cells that ameliorate pulmonary fibrosis

“…In vitro, although AEC-II cells can give rise to alveolar-like colonies, they possess limited clonogenic capacity that decreases with passaging. 47 Importantly, their number and function decline with age and in certain pathological conditions, 48,49 including IPF. 50 To determine whether interrupted reprogramming is able to rescue the in vitro limited clonogenic capacity of AEC-II cells, we isolated AEC-II cells from R26-rtTA/Col1a1::tetO-4F2A double transgenic mice 51 enabling expression of OSKM following treatment with doxycycline (Dox).…”

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

“…Indeed, one or more of the typical cellular ageing hallmarks, such as oxidative stress or activation of DNA damage, senescence and SASP pathways, has been reported to occur with ageing in hMSCs, VSMCs, haematopoietic stem cells (HSCs), skeletal muscle cells and neuronal stem cells 143,147 . The detrimental effects of these hallmarks on stem cells is demonstrated by the decreased regrowth of lung and pancreatic tissues, which have naturally high regenerative potential, upon partial resection in aged humans compared with that in young adults 148,149 . Conversely, silencing p16, activating SIRT1, blocking SASP effects by overexpressing an IL-1 receptor antagonist or reducing ROS by overexpressing the anti-oxidant superoxide dismutase 2 improves the regenerative capacity of hMSCs and HSCs as well as neuronal, intestinal and muscle stem cells 143,147 .…”

“…In T2D, hMSCs may have diminished proliferative and differentiation capacity, and hMSC- and pancreatic-specific stem cell activity is beneficial to pancreatic β-cell mass and function 148 . Furthermore, the differentiation potential of lung-specific stem cells is dysregulated in ageing-associated idiopathic pulmonary fibrosis, and functional hMSCs aid in the repair of osteoporotic bone fractures 143,149 . Although the contribution of cardiac and neuronal stem cells to the turnover of terminally differentiated myocytes and neurons remains unclear 147,151 , their beneficial immunoregulatory secretory effects have been established and shown to alleviate cognitive defects in mouse models of Alzheimer disease upon injection of hMSCs 147,151 .…”