Growth and aging: a common molecular mechanism

Mikhail V. Blagosklonny1 , Michael N. Hall2

• 1 Roswell Park Cancer Institute, Buffalo, NY 14263, USA
• 2 Biozentrum, University of Basel, CH4056 Basel, Switzerland

Received: March 1, 2009       Accepted: April 20, 2009       Published: April 20, 2009

https://doi.org/10.18632/aging.100040
How to Cite

Abstract

It is commonly assumed that growth and aging are somehow linked, but the nature of this link has been elusive. Here we review the aging process as a continuation of TOR-driven growth. TOR is absolutely essential for developmental growth, but upon completion of development it causes aging and age-related diseases. Thus, the nutrient-sensing and growth-promoting TOR signaling pathway may provide a molecular link between growth and aging that is universal from yeast to human.

Introduction

At first glance, growth and aging appear to be opposites. Growth is energy-driven synthesis of macromolecules from simple nutrients, an increase of order and a decrease of entropy. Aging is decay, a loss of order and a rise of entropy. Seemingly, growth and aging are mutually exclusive. Forever proliferating cells, such as legendary hydras, do not show signs of aging. In contrast, when an organism ceases to grow, aging follows. However, manipulations that decrease growth also decrease aging and prolong life span. For example, calorie restriction (reduced nutrient intake) reduces growth and increases longevity in diverse species from yeast to mice. Rapamycin, which inhibits growth in yeast, decelerates yeast aging. Inactivation of the growth-promoting insulin/IGF-1 signaling pathway increases life span, from worms to mice. Why do growth-inhibiting conditions slow down aging? Are growth and aging mechanistically similar? As we discuss here, growth and aging may not be opposites but rather a continuation of one another driven by the same molecular pathway. Aging and growth may be linked in a way that growth produces aging. In other words, excessive growth is a driving force for aging. The molecular pathway that drives both growth and aging appears to be the evolutionarily conserved TOR (target of rapamycin) pathway.

The TOR pathway

TOR (Target Of Rapamycin), as its name indicates, was originally discovered, in yeast, as the target of the antifungal drug rapamycin. Rapamycin is a natural secondary metabolite produced by soil bacteria to inhibit growth of fungal competitors. Thus, it is a mirror image of penicillin that is produced by fungi to inhibit bacterial growth. Remarkably, TOR is structurally and functionally conserved from yeast to human (including worms, flies, plants and mice) as an essential, central controller of cell growth [1]. 

TOR in mammals (mTOR) controls cell growth and metabolism in response to nutrients (e.g., amino acids), growth factors (e.g., insulin, IGF-1, PDGF), and cellular energy status (ATP). Nutrients are the dominant TOR input as high levels of amino acids can compensate for an absence of the other mTOR inputs but not vice versa [2], and only nutrients activate TOR in unicellular organisms. The growth factor signaling pathway, grafted onto the more ancestral nutrient sensitive TOR pathway, co-evolved with multicellularity. TOR activates cell growth by positively and negatively regulating several anabolic and catabolic processes, respectively, that collectively determine mass accumulation. The anabolic processes include transcription, protein synthesis, ribosome biogenesis, nutrient transport, and mitochondrial metabolism. Conversely, TOR negatively regulates catabolic processes such as mRNA degradation, ubiquitin-dependent proteolysis, and autophagy. TOR is an atypical serine/threonine kinase that is found in two functionally and structurally distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in mammals), each of which signals via a different set of effector pathways. TORC1 is rapamycin sensitive whereas TORC2 is rapamycin insensitive. The best-characterized phosphorylation substrates of mTOR are S6K and 4E-BP1 via which mTORC1 controls translation, and Akt/PKB via which mTORC2 controls cell survival and other processes [3]. Like TOR itself, the two TOR complexes and the overall architecture of the TOR signaling network appear to be conserved from yeast to human [1,4]. TOR and many of the processes it controls have also been shown to play a role in aging (in addition to growth) in a wide variety of organisms, as described below. https://www.aging-us.com/article/100040/text

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