Date Published: August 07, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Miren Revuelta, Ander Matheu.
Aging is responsible for changes in mammalian tissues that result in an imbalance to tissue homeostasis and a decline in the regeneration capacity of organs due to stem cell exhaustion. Autophagy is a constitutive pathway necessary to degrade damaged organelles and protein aggregates. Autophagy is one of the hallmarks of aging, which involves a decline in the number and functionality of stem cells. Recent studies show that stem cells require autophagy to get rid of cellular waste produced during the quiescent stage. In particular, two independent studies in muscle and hematopoietic stem cells demonstrate the relevance of the autophagy impairment for stem cell exhaustion and aging. In this review, we summarize the main results of these works, which helped to elucidate the impact of autophagy in stem cell activity as well as in age‐associated diseases.
Aging is a multifaceted process that leads to alterations in tissue structure and the decline of many functions and activities in mammals. Proteostasis is necessary for most cellular functions, such as genetic replication, catalysis of metabolic reactions, and the immune response. Impairments in proteostasis can lead to toxic aggregations and accumulation of unwanted proteins resulting in cellular dysfunction (Powers et al., 2009). The maintenance of tissue homeostasis and the regenerative capacity after an injury depends on tissue‐specific stem cells (Oh et al., 2014). The elucidation of the hallmarks of aging by Lopez‐Otin and collaborators identified the impairment of protein homeostasis and stem cell exhaustion as major processes involved in the decline of the regenerative potential capacity linked to the accumulation of age‐associated damage. In particular, loss of proteostasis was considered a primary hallmark, whilst stem cell exhaustion was an integrative hallmark (Lopez‐Otin et al., 2013).
Aging results from the accumulation of cellular damage promoted by chronic stresses of small magnitude. Therefore, being a sensor of stress, autophagy has been linked to aging. Several studies have described a decline in autophagy activity (measured by altered autophagic flux, LC3 and p62 protein expression) as well as expression of autophagy gene such as Atg1, Atg5, Atg6, Atg7, Atg8, and Atg12 in response to aging in several animal models and human tissues. The majority of these works have focused on MA, the most studied form of autophagic process, but there have also been studies showing a decline in CMA, particularly in the liver and the central nervous system, which have been linked to decreased function in these organs (Cuervo, 2008; Rubinsztein et al., 2011). Longevity studies with gain and loss of autophagy genes in animal models such as yeast, C. elegans, Drosophila and mice, support a direct role for autophagy in the aging process. For example, genetic experiments demonstrate a requirement for key autophagy regulators such as Atg1/ULK1, Atg7, Atg8, Atg11, or Beclin1 as their inactivation or reduction in levels accelerated aging and reduced lifespan in different animal models. These phenotypes have been associated with appearance of age‐associated pathologies such as damaged mitochondria, reduced cardiac performance, lipid accumulation, and muscle degeneration. In contrast, overexpression of Atg5 or Atg12, among others, extended life span in several species and delayed the decline of multiple features of aging such as mitochondrial maintenance or motor function (Madeo et al., 2010, 2015). Clear proof for the impact of CMA in aging came with the generation of transgenic mice harboring an extra copy of LAMP2a, a CMA receptor in lysosomal membrane, that specifically targeted to the liver, and that demonstrated an improved cellular homeostasis and hepatic function in aged mice (Zhang & Cuervo, 2008). In addition, genetic studies have revealed that impairment of MA, via inactivation of various Atg genes, is involved, along with other causative factors, in age‐associated pathologies, including neurodegenerative diseases, cancer, cardiac malfunction, reduced muscle mass, and sarcopenia (Hara et al., 2006; Rubinsztein et al., 2011; Zhou et al., 2017). A decline in CMA activity has been associated with age‐related pathologies such as Alzheimer’s and Parkinson’s diseases (Cuervo & Wong, 2014). Further support for a link between autophagy and aging comes from studies involving caloric restriction, the most effective strategy to induce autophagy, that is also the most efficient and reproducible intervention known to increase lifespan and delay aging in several organisms ranging from yeast to primates (Lopez‐Otin et al., 2013). Caloric restriction induces the inhibition of mTOR complex 1 and activation of AMPK, which in turn results in the activation of the ULK1 complex. Caloric restriction also stimulates SIRT1, which is known to activate many essential autophagic proteins. Interestingly, pharmacological stimulation of MA, via the administration of the mTOR inhibitor rapamycin (an agent that mimic the effects of caloric restriction), extends lifespan and presents anti‐aging effects in several animal models such as yeast, flies and mice (Madeo et al., 2010; Lopez‐Otin et al., 2013). Similarly, spermidine, a natural inducor of autophagy, maintains long‐lasting immunity and slows down progression of neurodegenerative diseases associated with age. These autophagy‐dependent effects are dependent on Atg7 gene function (Puleston et al., 2014; Bhukel et al., 2017). All this evidence supports the assertion that autophagy is involved in longevity, aging and development of age‐associated pathologies and has encouraged the scientific community to identify the precise role and molecular mechanisms of autophagy in aging, as targeting autophagy could be a novel therapy against aging and age‐related diseases.
How autophagy decreases with age remains unclear and under intense investigation. Recent works carried on aged muscle stem cells (MSC) and hematopoietic stem cells (HSC) have revealed the impairment of MA in stem cell activity with aging (Fig. 1A,B). Moreover, these studies have confirmed that correct functioning of MA is necessary to maintain the appropriate blood system and muscle development and to allow adult stem cell to survive under metabolic stress (Garcia‐Prat et al., 2016; Ho et al., 2017).
In the last decade, there have been incredible advances in understanding stem cell aging and the molecular mechanisms underlying this process. Indeed, the induction of p16Ink4a senescence marker (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006), the activation of p38 MAPKinase (Bernet et al., 2014; Cosgrove et al., 2014), and STAT3 (Price et al., 2014; Tierney et al., 2014) pathways are nowadays well‐recognized critical regulators of stem cell activity and there are different strategies currently being tested targeting them as therapy against stem cells and age‐related diseases (Oh et al., 2014). The novel works of Garcia‐Prat and Ho offers relevant new information regarding the autophagy malfunctioning in aged stem cell and the effect of reversing this disorder in two independent stem cell niches. Whether these results can be translated to other stem cell niches will be surely determined in the future. In addition, it will also be important to elucidate whether CMA or micro‐autophagy play any role in stem cell aging. These works uncovered the requirement of correct autophagy activity for stem cell function and postulated the pharmacological restoration of autophagy as a novel strategy to boost stem cell activity for regenerative medicine and aging. The discovery that rapamycin extends mammalian lifespan and activates autophagy is promising because it represents the first demonstration of pharmacological extension of maximal lifespan linked to autophagy in mammalian species. Rapamycin and its derivatives are FDA‐approved, are used clinically to prevent organ rejection after kidney transplantation, and are also being tested in clinical trials for the treatment of several cancers and neurodegenerative disorders. Therefore, considerable experience exists with the application of this compound in the clinic. However, it is important to first unravel whether the rapamycin‐promoted lifespan extension is dependent on autophagy effects or not.
This work is supported by grants from the Instituto Salud Carlos III and FEDER Funds (CP16/00039, PI16/01580, DTS16/0184), Diputacion Foral Gipuzkoa and Marie Curie CIG (2012/712404) to the laboratory of AM.
The authors declare no competing financial interests.