Researchers have been talking about therapies based on enhanced levels of autophagy for about as long as I've been paying attention to the field of aging research. Autophagy is a collection of processes responsible for breaking down and recycling damaged structures and unwanted proteins in cells. More aggressively removing harmful or malfunctioning cellular systems and wastes reduces the amount of time they exist to cause problems, and results in better functioning of cells and tissues. Ultimately, more autophagy modestly slows aging and allows individuals to live longer. Many of the varied methods of manipulating metabolism to slow aging demonstrated over the past few decades appear to either depend on autophagy or include increased autophagy among their mechanisms of action.
Despite all of the talking - and the many papers and years of work examining various controlling mechanisms associated with autophagy - there is as yet no real progress towards therapeutics that work via the deliberate, targeted upregulation of autophagy. That is if we don't count things like calorie restriction mimetics, which improve autophagy along the way of changing many other aspects of metabolism. Calorie restriction itself appears to stop producing benefits to health if autophagy is disabled. Calorie restriction mimetics are not really all that solidified yet as a class of therapeutic, however. The most compelling, such as mTOR inhibitors, have significant side-effects that are still being worked around. The rest are largely so marginal or the data for positive effects in animal studies so unreliable as to be unworthy of serious consideration in a world in which one can just eat less and definitely benefit from it.
The editorial here (still in PDF format only at the time of writing) presents a more recent example of research aimed at identifying targets for the therapeutic enhancement of autophagy. It is similar in tone and scope to a dozen others I've seen over the years, and little has come of them as of yet - even the important work from a decade ago, showing restoration of liver function in old mice. The research community, for reasons that remain unclear to me, seems challenged when it comes to moving beyond mapping and investigation in order to build something of practical use on the foundation provided by this part of the field.
Increased oxidative stress and loss of proteostasis are characteristics of aging. Failure to remove the oxidative stress-damaged components has been recognized to play critical roles in the pathophysiology of common age-related disorders including neurodegenerative disease and cardiovascular diseases such as myocardial infarction and heart failure. Strategies to diminish oxidative stress or effectively eliminate oxidative-damaged intracellular proteins may therefore provide novel therapeutic option for many age-related diseases.
Chaperone-mediated autophagy (CMA) allows for selective degradation of soluble proteins in lysosomes, contributing to the cellular quality control and maintenance of cellular energetic balance. CMA substrate proteins are targeted by the chaperone hsc70 to the lysosomal surface where, upon binding to the lysosome-associated membrane protein type 2A (LAMP2A), they are translocated into the lysosomal lumen for degradation. CMA is activated by oxidative stress to facilitate degradation of damaged proteins, thereby eliminating the insults of oxidative stress. Given the fact that CMA activity declines with age, and oxidative damage in cells increases during aging, CMA activators hold the potential for development as a new generation of treatment option for age-related diseases.
In our recent study, we identified that humanin (HN), an antiapoptotic, mitochondria-associated peptide is an endogenous CMA activator. We demonstrated that HN protects multiple cell types including cardiomyoblasts, primary cardiomyocytes and dopaminergic neuronal cells from oxidative stress-induced cell death in a CMA dependent manner. In fact, this protective effect is lost in CMA-incompetent cells (LAMP-2A knockdown). Both exogenously added HN as well as the endogenously generated HN cooperate in CMA activation. Thus, knockdown of endogenous HN decreases CMA activation in response to oxidative stress. Both endogenous and exogenous HN localize at the lysosomal membrane where they cooperate to enhance CMA efficiency. HN acts by stabilizing binding of the chaperone HSP90 to the upcoming substrates at the cytosolic side of lysosomal membrane.
Our study provided the first evidence that regulatory signals from mitochondria can control CMA. We propose that while generating reactive oxygen species (ROS) from metabolism, mitochondria simultaneously initiates signals such as HN to eliminate ROS by increasing antioxidant enzyme activities, and decrease oxidative insults by activating CMA, and that perturbations in this process could cause accumulation of oxidative damage leading to cell death and human diseases. It is interesting to note that HN and CMA both decline with age and that genetic correction of the CMA defect in livers from old mice was effective in improving hepatic homeostasis, conferring higher resistance to stress and improved organ function.
We propose that interventions aimed to enhance mitochondrial peptide HN levels could have a similar effect, and protect against oxidative stress by enhancing removal of oxidative-damage proteins through CMA. Whether this is a unique function of HN, or is shared by other mitochondria-encoded peptides such as small humanin like peptides (SHLPS) requires future investigation. Efforts should be directed to testing a possible protective effect of HN in age-related diseases with a primary defect on CMA such as Parkinson's disease.