Taking life-extending drug Rapamycin to the next level

Life extension studies fly the flag for Rapamycin – a clever drug with humble origins – now a US research team is taking matters further.

A new bacteria – Streptomyces – was discovered in Easter Island bacteria in 1965 and a new drug – Rapamycin – that was named after the traditional name for this remote volcanic island of Rapa Nui, was successfully isolated in 1972.

Longevity.Technology: Rapamycin seems to be the Swiss Army Knife of drugs for Longevity; from stopping cancer to halting aging and from protecting the brain from neurodegenerative diseases to preventing inflammation. It is the only drug so far able to prolong lifespan in four diverse species – mice, flies, yeast and worms [1]. Here we address what the next development could be.

The TRL score for this Longevity.Technology domain is currently set at: ‘Technology has completed initial trials and demonstrates preliminary safety data.’

The TRL score for the technology addressed in this article is: ‘Technology refined and ready for initial human trials.’

Rapamycin has been marketed as an immunosuppressant, given to transplant patients to mitigate organ rejection [2], but it has another superpower. Rapamycin is able to block a protein named mTOR (mechanistic target of Rapamycin) by linking on to its intracellular receptor FKBP12 and then this complex binds directly with the FKBP12-Rapamycin Binding (FRB) switching off its activity [3].

mTOR is a kinase that links with other proteins, acting like a hub for cellular communication or a nexus for cell biology. It is a key influence in how our cells develop and divide; how proteins are made and distributed, how mitochondria provide cells with energy and how cells recycle and remove unwanted waste molecules. mTOR senses the amount of energy, nutrition and oxygen in a cell and can alter this by signalling other pathways [4]. mTOR also regulates cell growth [5] and can trigger cell death (apoptosis) [6]. During cell growth, mTOR activates the secretion of a large number of bioactive molecules that can promote cancer growth [7].

mTOR is part of many crucial pathways and by blocking it, scientists can inhibit cell growth meaning it can prevent the proliferation of some cancers. Blocking mTOR with Rapamycin can also prevent cell death, meaning that aging can be slowed or even stopped. Also, when mTOR is inhibited, the process of autophagy – when the body’s refuse collectors, the lysosomes, get to work cleaning up wonky proteins and damaged cell structures, recycling them into sugars for reuse by the cell [8]. Aging clogs up cells with broken and dysfunctional organelles and proteins and the autophagy process attempts to keep these to a minimum. Neurodegenerative diseases such as Alzheimer’s Disease and Parkinson’s Disease are especially associated with this cluttering up of cells by dysfunctional bits and pieces.

Research on Rapamycin is also leading to new breakthroughs; Haoxing Xu, a professor in the University of Michigan Department of Molecular, Cellular and Developmental Biology and his team have discovered that Rapamycin also targets another cellular pathway, TRPML1, a calcium ion channel that is situated on the lysosomal membrane [9]. TRPML1 is vital in the regulation of lysome function; as Xu explains: “Without this channel, you get neurodegeneration. If you stimulate the channel, it’s anti-neurodegeneration [10].”

The team found that by using a sophisticated lysosome patch they could apply rapamycin to lysosomes and observe that that the TRPML1 channel was opened regardless of whether mTOR was active or not. The rapamycin also enhanced the autophagy process, so this is of particular relevance to the fields of research into neurodegeneration diseases.

Co-lead author Wei Chan said: “We think lysosomal TRPML1 may contribute significantly to the neuroprotective and anti-aging effects of rapamycin. The identification of a new target of rapamycin offers an insight in developing the next generation of rapamycin, which will have a more specific effect on neurodegenerative disease [11].”