To date, the most reliable, best-researched way to extend life span is through the practice of CR, which involves reducing calorie intake while simultaneously maintaining good nutritional status. Indeed, epidemiological and experimental data indicate that diet plays a central role in the pathogenesis of many age-associated chronic diseases, as well as in the biology of aging itself (see Figure 1). Human studies indicate that long-term CR with adequate intake of nutrients results in several metabolic adaptations that reduce the risk of developing type 2 diabetes, hypertension, cardiovascular disease, and cancer22.

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 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 changes40. Another study evaluated the effects of high-fat diet (HFD) in relation to lung aging41. As known, HFD decreases the lifespan of mice and is a risk factor for several human diseases. Indeed, this study revealed that HFD induces several histological, inflammatory, and functional changes in the lung, and exacerbates aging-induced lung inflammation and mitochondrial deterioration41. Of note, although a body of literature suggested the development of emphysema following severe CR and led to the notion of “nutritional emphysema” that might have relevance in COPD patients, neither the mechanics nor the histology showed any evidence of emphysema-like changes with severe CR in a murine study42.

Resveratrol (a substance found in red grapes and other plants), is one potential CR mimetics that may have beneficial effects against numerous diseases such as type 2 diabetes, cardiovascular disease, and cancer in tissue culture and animal models. Interestingly, a recent discovery suggested that the metabolic effects of resveratrol may be mediated by inhibiting cAMP phosphodiesterases (PDEs), particularly PDE443. Roflumilast, belonging to the class of PDE4 inhibitors, is currently used to treat COPD due to its ability to inhibit inflammatory cell responses44. Combined together, these findings may suggest that PDE4-related molecular pathways might be involved both in the biology of lung aging and COPD pathogenesis.

The growth hormone/IGF axis can be manipulated in animal models to promote longevity; IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of aging-associated diseases in humans45. Indeed, a recent study which evaluated lung function parameters in a large cohort of patients with acromegaly, revealed that these patients showed signs of small airway obstruction46. However, the idea of inhibiting the growth hormone/IGF-I axis for the management of COPD may not be straightforward. Many patients with COPD are malnourished, and this affects respiratory muscle function and prognosis for survival adversely. 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 COPD47, although significant beneficial effects were not observed48.

It is well established that multiple mesenchymal growth factors have been shown to be exaggerated in several fibrotic lung disorders including IPF, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis49. These growth factors include transforming growth factor (TGF)-β, IGF-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors. Another study demonstrated IGFBPs may play an important role in the development of fibrosis in IPF50.

A highly conserved protein kinase, mTOR (originally known as mammalian target of rapamycin), is continuously highlighted as a key modulator of aging in evolutionarily divergent organisms, ranging from yeast to rodents, and it is likely that this function has been conserved to some extent in humans5152. A series of studies showed that rapamycin extended lifespan in yeast, nematodes, fruit flies and mice, firmly establishing mTOR signaling as a central, evolutionarily conserved regulator of longevity. Accordingly, much effort has been applied to defining the underlying mechanisms as to how mTOR signaling plays as a key modulator of aging-associated lung disorders.

Rtp801, a stress-related protein triggered by adverse environmental conditions and inhibits mTOR, has recently been identified to represent a major molecular sensor and mediator of cigarette smoke-induced lung injury53. In this study, Rtp801 mRNA and protein were overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. Mechanistic experiments found that Rtp801 was necessary and sufficient for nuclear factor-κB activation, alveolar inflammation, oxidative stress and apoptosis of alveolar septal cells, which have been identified to be key molecular mechanisms for COPD pathogenesis53. Demonstrating that mTOR activation was sufficient to induce lung cell senescence and mimic COPD lung alterations, with the rapid development of lung emphysema, pulmonary hypertension, and inflammation, the results from this study support a causal relationship between mTOR activation, lung cell senescence, and lung alterations in COPD54. In line with this, it was recently shown that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)–induced cellular senescence via dysregulation of mTOR and mitochondrial integrity55. Contrasting data exist, however. A study demonstrated that mTOR suppresses CS-induced inflammation through modulation of autophagy, apoptosis, and necroptosis, suggesting that activation of mTOR may represent a novel therapeutic strategy for COPD56. Another study suggested that particulate matter (PM) may inactivate mTOR signaling and promote the subsequent autophagy-mediated epithelial injury in PM-induced airway inflammation57. This apparent discrepancy may be due to the complex and heterogenic enzymatic pathway of mTOR signaling, implying that translation on the use of mTOR inhibitors to COPD therapy requires a more in-depth knowledge of mTOR signaling58.

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 IPF lung fibroblasts59. In addition, a recent meta-analysis of genome-wide studies across three independent cohorts reported the importance of mTOR signaling in lung fibrosis60. Interestingly, by demonstrating that the alteration of canonical mTOR/phosphoinositide 3-kinase (PI3K)/AKT signaling is causally associated with increased Yes-associated protein (YAP) activity in respiratory epithelial cells in lungs of patients with IPF, a recent study expanded the functional significance of mTOR into Hippo/YAP signaling61. As known, Hippo/YAP pathway is a recently identified signaling cascade that plays an evolutionarily conserved role in the regulation of cell proliferation and differentiation during organogenesis and tissue repair62. Thus, YAP and mTOR/p-S6 signaling pathways may interact to induce cell proliferation and migration and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF.

Of note, a recent study suggested that the mTORC1/4E-BP1 axis may represent a critical signaling node during fibrogenesis63. In this study, rapamycin-insensitive mTORC1 signaling via 4E-BP1 was shown to be a critical pathway for TGF-β1 stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/AKT signaling was not required63. This observation may have significant implication because, currently, pan-PI3K/mTOR inhibition is under clinical evaluation to test a therapeutic potential of targeting mTOR signaling in subjects with IPF6465.

Taken together, alterations in mTOR signaling, which are associated with dysregulation of autophagy, inflammation, cell growth, and survival, may lead to the development of lung fibrosis66. Given complicated nature of mTOR signaling, it would be critical to continue basic research to elucidate this further and refine specific molecular targets involved in mTOR signaling for the development of novel IPF therapeutics.

Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMPK complex. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy, positioning the AMPK complex as a central mediator of the cellular response to energetic stress and mitochondrial insults leading to the coordination of multiple features of autophagy and mitochondrial biology67.

Sirtuins (SIRTs) are well-known mediators of aging68. Suppression of cellular senescence by SIRTs is mainly mediated through delaying age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair69. In addition, SIRTs modulate the organismal lifespan by interacting with several lifespan regulating signaling pathways including insulin/IGF-1 signaling pathway and AMPK69. For example, AMPK was known to control the expression of genes involved in energy metabolism by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1, indicating the AMPK-induced SIRT1-mediated deacetylation may explain many of the convergent biological effects of AMPK and SIRT170. As such, recent data obtained from lung aging-associated disorders in relation to AMPK or SIRTs are discussed under the same sub-section, although the functional roles of these two molecules are not entirely dependent each other in the regulation of aging hallmarks.

SIRT1 has been identified to be reduced in lungs of patients with COPD71. In addition, SIRT1 activation attenuated stress-induced premature cellular senescence and protected against emphysema induced by CS and elastase in mice, implicating that activation of SIRT1 may be an attractive therapeutic strategy in COPD/emphysema72. Another member of the SIRT family, SIRT6, a histone deacetylase, antagonizes cellular senescence, through the attenuation of IGF-AKT signaling. In line with this, a study demonstrated that SIRT6 expression levels were decreased in lung homogenates from COPD patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 sec/forced vital capacity, implicating that SIRT6 might be involved in COPD pathogenesis via its regulation of cellular senescence which can be attributed to IGF-AKT-mTOR signaling73.

A study suggested that accelerated epithelial senescence which can be antagonized by SIRT6 might play a role in IPF pathogenesis through perpetuating abnormal epithelialmesenchymal interactions74. 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 SIRT775.

Overall, SIRTs have been identified to regulate inflammation, aging (life span and health span), mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. Hence, various novel ways to activate sirtuins, either directly or indirectly, may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases76.

Metformin has been shown to significantly increase lifespan and delay the onset of age-associated decline in several experimental models, and a growing body of evidence from clinical trials suggests that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, cancer, chronic inflammation, and frailty77. Regarding its pharmacologic action, it is important to note that metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug, requiring further elucidation of the underlying mechanisms of its action78.

COPD is often associated with type 2 diabetes mellitus (T2DM). Because metformin is a first-line treatment for most patients with T2DM, a study was aimed at investigating the effect of metformin on health care utilizations in patients with coexisting COPD and diabetes mellitus (DM). Interestingly, the use of metformin in patients with coexisting COPD and DM was associated with fewer COPD-specific emergency room visits and hospitalizations79. Another systematic review of pubic databases found also that metformin may benefit patients with COPD and T2DM by improving overall health status including symptoms, hospitalizations, and mortality80.

A therapeutic potential of metformin in IPF was implicated in a recent study81. This study demonstrated that, in humans with IPF and in an experimental mouse model of lung fibrosis, AMPK activity was lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts81. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF displayed lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In addition, 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 myofibroblasts81. Similar evidence was provided by another report which demonstrated that metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGF-β1 action, suppressing collagen formation, and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients82. When a post hoc analysis was undertaken to assess the effect of metformin on clinically relevant outcomes in patients with IPF, however, metformin showed no effect on clinically relevant outcomes in patients with IPF83.

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 the mechanism(s) responsible for inflammaging and its causal role in aging and age-related diseases are still elusive, emerging evidence suggests that one of basic processes that may contribute to age-related dysfunction and chronic sterile inflammation is cellular senescence84. Indeed, it has been demonstrated that chronic inflammation may derive, at least in part, from senescent cells: senescent cells secrete proinflammatory cytokines, chemokines, and proteases, termed the senescence-associated secretory phenotype84. In addition, age-associated accumulation of damage-associated molecular patterns has been proposed as a potential driver of inflammaging2585.

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 possibility86. The lungs of old mice have elevated levels of proinflammatory cytokines and a resident population of highly activated pulmonary macrophages that are refractory to further activation by interferon-γ86. Another study suggested that inflammaging per se, which is induced over aging, could increase susceptibility to cigarette smoke-induced COPD87. The data from this murine experimental study revealed that age-induced lung inflammation is further elevated after CS exposure in old mice. An age-induced change in immune cells might play as a susceptibility factor to CS exposure, accelerating the pathophysiological hallmarks of COPD87.