Age-Slowing Interventions in the Context of Lung Aging
Researchers here consider a very conservative set of interventions known to modestly slow the progression of aging in laboratory species, largely by altering metabolism to upregulate beneficial cellular stress responses. The researchers look through the lens of lung aging, specifically, reviewing the evidence for these therapies to slow the deterioration in lung function and onset of lung disease in older individuals, or to be the basis for treating established lung disease.
To date, the most reliable, best-researched way to extend life span is through the practice of calorie restriction (CR), which involves reducing calorie intake while simultaneously maintaining good nutritional status. Although the effects of diet on lung aging per se has thus far been rarely studied, several studies suggest a significant role of dietary modulation on lung aging. When a study examined the effects of aging on lung epithelial cells and stem cells and the effect of CR on young and old lungs, CR was identified to induce several potentially beneficial changes in lung epithelial cells, even when it is initiated at an older age, including reversal of some aging-induced changes.
The growth hormone/IGF axis can be manipulated in animal models to promote longevity; IGF-related proteins have also been implicated in risk of aging-associated diseases in humans. Indeed, a recent study which evaluated lung function parameters in a large cohort of patients with acromegaly due to excess growth hormone, revealed that these patients showed signs of small airway obstruction. However, the idea of inhibiting the growth hormone/IGF-I axis for the management of chronic obstructive pulmonary disease (COPD) may not be straightforward. Previously, there were attempts to use recombinant human growth hormone treatment which has been proposed to improve nitrogen balance and to increase muscle strength in patients with COPD, although significant beneficial effects were not observed.
A series of studies showed that mTOR inhibitor rapamycin extended lifespan in yeast, nematodes, fruit flies and mice, firmly establishing mTOR signaling as a central, evolutionarily conserved regulator of longevity. Aging may affect adaptive responses to stress decreasing autophagy through activation of mTORC1 in lung fibroblasts, and this mTOR activation may contribute to the resistance to cell death in idiopathic pulmonary fibrosis (IPF) lung fibroblasts. In addition, a recent metaanalysis of genome-wide studies across three independent cohorts reported the importance of mTOR signaling in lung fibrosis.
Sirtuins (SIRTs) are well-known mediators of aging. Suppression of cellular senescence by SIRTs is mainly mediated through delaying age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair. A study suggested that accelerated epithelial senescence which can be antagonized by SIRT6 might play a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions. When the mRNA and protein levels of all seven known sirtuins (SIRT1-7) were assessed in primary lung fibroblasts from patients with IPF and systemic sclerosis-associated interstitial lung disease in comparison with lung fibroblasts from healthy controls, these unbiased tests revealed a tendency for all SIRTs to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7.
Metformin has been shown to increase lifespan and delay the onset of age-associated decline in several experimental models. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerated the resolution of well-established fibrosis in an AMPK-dependent manner, further supporting a role for metformin to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.
An age-associated increase in chronic, low-grade sterile inflammation termed "inflammaging" is a characteristic feature of mammalian aging that shows a strong association with occurrence of various age-associated diseases. Although it is not clearly defined whether the pulmonary environment becomes inflammatory with increasing age in humans, an in vivo study using a murine model organism suggests this possibility. The lungs of old mice have elevated levels of proinflammatory cytokines and a resident population of highly activated pulmonary macrophages.