The activities of mTOR are well researched, given that mTOR inhibition slows aging in a number of species. This is one of the more prominent areas of research and development to emerge from the study of beneficial stress responses such as that produced by the practice of calorie restriction. The mTOR protein participates in cellular metabolism through a pair of protein complexes, and much of the work to date has focused on the protein complex mTORC1 rather than mTORC2.
The present consensus (though not unchallenged) is that general inhibition of mTOR, such as via the use of rapamycin, is problematic because harmful effects arise from inhibition of mTORC2, offsetting the benefits due to inhibition of mTORC1. Certainly, it is the case that inhibiting mTORC2 alone shortens lifespan in laboratory animals, while inhibiting mTORC1 alone slows aging and extends life. Thus the development of drugs based on this research has focused on specific inhibition of mTORC1; several companies have a pipeline of small molecule therapies in later stage trials.
Researchers here show that increased mTORC2 activity boosts autophagy and improves cardiac function in middle-aged flies, suggesting that the current industry of mTORC1 inhibition will soon enough be joined by an industry of mTORC2 upregulation. I remain unconvinced that the effect sizes in humans resulting from upregulated autophagy will be large enough to merit the strong focus placed on this line of research and development, at a time in which most work on more promising rejuvenation therapies continues to languish in comparison, but we shall see how it all turns out soon enough.
The researchers' approach starts with autophagy, a cellular "cleanup process" that removes and recycles damaged proteins and organelles. The autophagy process slows with age, which can lead to the weakening of cardiac muscles. The research team looked at a key genetic pathway conserved in virtually all organisms on Earth related to autophagy that balances organism growth with nutrient intake. This pathway, called mechanistic target of rapamycin (or mTOR), has long been linked to tissue aging. One of two complexes that underlie the mTOR pathway, referred to as mTORC2, decreases with age as autophagy declines. But the researchers found that transgenically boosting mTORC2 strengthens heart muscles of older fruit flies. "Boosting the complex almost fully restored heart function."
The discovery that enhancing mTORC2 slows the decline of the critical autophagy process could have big implications for how doctors treat patients with heart disease, one of the leading causes of the death. While flies and humans might seem to be worlds apart evolutionarily, the two species' hearts age in a similar fashion. By middle age, cardiac muscles in both species tend to contract with less strength and regularity.
Age-related impairment of macroautophagy/autophagy and loss of cardiac tissue homeostasis contribute significantly to cardiovascular diseases later in life. MTOR (mechanistic target of rapamycin kinase) signaling is the most well-known regulator of autophagy, cellular homeostasis, and longevity. The MTOR signaling consists of two structurally and functionally distinct multiprotein complexes, MTORC1 and MTORC2. While MTORC1 is well characterized but the role of MTORC2 in aging and autophagy remains poorly understood.
Here we identified TGFB-INHB/activin signaling as a novel upstream regulator of MTORC2 to control autophagy and cardiac health during aging. Using Drosophila heart as a model system, we show that cardiac-specific knockdown of INHB/activin-like protein daw induces autophagy and alleviates age-related heart dysfunction, including cardiac arrhythmias and bradycardia. Interestingly, the downregulation of daw activates TORC2 signaling to regulate cardiac autophagy. Activation of TORC2 alone through overexpressing its subunit protein rictor promotes autophagic flux and preserves cardiac function with aging. In contrast, activation of TORC1 does not block autophagy induction in daw knockdown flies. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulation of these pathways in the heart has systemic effects on longevity control.