Take out the cellular trash - Biological clean-up mechanisms could hold the key to combating age-related disease. By Elie Dolgin - Nature
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Ageing
outlook
SAM FALCONER
Take out the cellular trash
demonstration that boosting the autophagy
machinery could promote longevity and
well-being in a mammal1.
“This was a proof of concept that it’s possi-
ble and it’s beneficial,” Sebti says. By breeding
Biological clean-up mechanisms could hold the key the autophagy-boosted mice together with
various mouse models of disease, her team
to combating age-related disease. By Elie Dolgin and others have found several more health-
S
promoting benefits. They have shown how
autophagy augmentation can preserve stem-
alwa Sebti was growing impatient. In and kidneys had less tissue scarring than cell function in the ageing mouse brain2, pre-
2014, she and her colleagues at the usual; spontaneous cancers were kept at bay; vent cognitive decline in a mouse model of
University of Texas Southwestern and the mice lived approximately 10% longer. Alzheimer’s disease3, and overcome ageing-
(UTSW) Medical Center in Dallas had As the data finally poured in, Sebti recalls related organ degeneration4.
begun tracking mice that had a genet- thinking to herself: “Oh wow, we have a strong Now, a growing number of biotechnology
ically enhanced ability to detoxify their cells. phenotype.” start-ups are trying to replicate those anti-
The goal was to test the anti-ageing effects of Other scientists had previously reported ageing effects by using drug compounds.
boosting autophagy, the biological house- similar age-defying benefits of enhanced Autophagy “is clearly a very fundamental
keeping process by which cells rid themselves autophagy in worms and flies. But the UTSW process that is linked to so many different
of damaged components. But it was almost study was breaking new ground. Spearheaded diseases,” says Peter Hamley, chief scientific
two years — a timespan roughly equivalent to by Beth Levine — a pioneering autophagy officer of Samsara Therapeutics in Oxford, UK.
70 years in humans — before the mice showed researcher who died of cancer in 2020 — and The company was set up in 2018 to treat neu-
any clear signs of health improvements. co-led by two of her former postdocs, Sebti rodegenerative and rare genetic diseases by
It was worth the wait. The animals’ hearts and Álvaro Fernández, it was the first definitive inducing or restoring the cellular degradation
Nature | Vol 601 | 20 January 2022 | S15
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Ageing
outlook
system. “It’s a big opportunity for drug discov- Because CMA relies on this highly specific
ery,” he says. signalling mechanism, drugs that stimulate
It’s also a big challenge. the process should “only degrade things that
Autophagy is often likened to the trash have been primed by the chaperone to be
management system of the cell. And just as degraded”, says Cuervo. This offers potential
municipal waste services involve collection, safety advantages over strategies designed
transportation and ultimately disposal, so to activate the less-discriminating cellular
too must the cell’s autophagy system follow demolition process implicated in the typical
a coordinated, multistep process. It first autophagy pathway, she argues.
requires cellular refuse to be bagged up inside The strategy is limited to protein targets
MARIAN VEJCIK/GETTY
sack-like structures known as phagophores. that engage with CMA, however. It is not an
These then mature into cargo containers option for other proteins, or for promoting
called autophagosomes, which fuse with deg- the clearance of other types of cellular debris,
radation hubs called lysosomes. Only then do such as entire organelles. For that, compa-
waste products get broken down. nies are exploring ways of inducing general
Any part of that cell-cleaning process could Parkinson’s disease can complicate normally autophagy, either in a non-selective manner
go wrong, and they often do as cells age. But simple activities, such as eating soup. or with an eye to eliminating structures such
if researchers do not fully understand what as mitochondria, the energy powerhouses of
aspects of autophagy are defective in any par- particular type of autophagy, helper proteins the cell.
ticular disease, drugs that modulate the wrong called chaperones interact with ‘destroy me’ Scientists at MindRank AI in Hangzhou,
parts of the pathway could do more harm than signals on target proteins. The chaperones China, for instance, used predictive algorithms
good. A therapy could, for instance, help the then shuttle their cargo directly to lysosomes, informed by machine learning to identify mol-
cell to package more trash. “But if your trash which break down the trash. ecules capable of promoting the degradation
compactor isn’t working properly, you’re just “CMA activation is exciting because it is of damaged mitochondria, a process known as
going to end up with a room full of trash bags,” a whole new therapeutic target that has not mitophagy. Their virtual screen yielded a list
says Tim Sargeant, who studies autophagy been explored clinically but appears to play of 18 compounds. Working with gerontolo-
at the South Australian Health and Medical a critical role in ageing biology,” says Joan gist Evandro Fang at the University of Oslo and
Research Institute in Adelaide. “That’s one of Mannick, head of research and development pharmacologist Jia-Hong Lu at the University
the dangers here.” at Life Biosciences. of Macau, the company then used human cells,
As a result, although some anti-ageing worms and mice to winnow this list down to
researchers and companies have gone all-in “One of the jokes is that two drug candidates, both of which target a
on targeting autophagy, others are more cir- protein called PINK1 — an important mediator
cumspect — especially given the lack of solid
my husband wants to start of mitochondrial quality control. Late last year,
evidence in people or even mouse models for taking them.” the researchers showed how the drugs helped
many of the proposed interventions. to improve memory in worm and mouse mod-
“It’s clear that, in general, maintaining auto- els of Alzheimer’s disease8.
phagy in particular cell types in the body is Cell biologist Ana María Cuervo has demon- This kind of approach has begun to attract
going to be beneficial for treating many dis- strated this in numerous disease contexts, interest from large pharmaceutical compa-
eases of ageing — so it makes sense to look at including conditions linked to metabolic dys- nies. Last year, for example, drug giant AbbVie,
autophagy activation,” says Stephen Helliwell, function and neurodegeneration. In 2013, she based in North Chicago, Illinois, agreed to
vice-president of discovery biology at Rejuve- and chemical biologist Evripidis Gavathiotis, purchase Mitokinin, a small biotech company
ron Life Sciences, a biotechnology company both at the Albert Einstein College of Medicine in San Francisco, California, that is develop-
based in Zurich, Switzerland. But, he adds, in New York City, identified a class of molecule ing PINK1-targeted agents for the treatment
“it’s one thing to do experiments in worms and that could stimulate CMA by promoting the of Parkinson’s disease. “By speeding up mito-
flies. It’s quite another to show that autophagy uptake of chaperone-guided garbage proteins phagy, you cause an increase in the clearance
manipulation is a safe and effective anti-ageing into the lysosome5. of defective mitochondria,” explains Nicholas
strategy in people.” In mouse models, these compounds have Hertz, Mitokinin’s co-founder and chief sci-
helped to ameliorate signs of Alzheimer’s dis- entific officer — and that seems to improve
Choose your target ease6 and have restored the functionality of neuronal function and brain health.
Some oncologists are striving to inhibit auto- blood-forming stem cells in the bone marrow7.
phagy because it can fuel the growth and The putative drugs worked so well, in fact, that A new purpose
spread of established tumours — although it “one of the jokes is that my husband wants to When it comes to drugs with broad autophagy-
is also known to stop new tumours from form- start taking them,” Cuervo says. inducing potential, several medicines already
ing. Those focused on other diseases of ageing, She and Gavathiotis licensed the technology being widely used seem to fit the bill. For exam-
however, have the opposite goal in mind: they to Life Biosciences and now serve as scientific ple, metformin, a common diabetes treatment,
are trying to give autophagy a lift, albeit in advisers to the company. With support from and the immunosuppressant rapamycin, which
different ways. the non-profit Alzheimer’s Drug Discovery is used to prevent transplant rejection, both
Some companies, such as Life Biosciences Foundation in New York City, Life Biosciences is fire up autophagy signalling through their
in Boston, Massachusetts, are taking aim at optimizing the compounds for use by humans. effects on mTOR, a master regulator of several
an atypical version of the process, known as Clinical trials involving people with age-related steps on the autophagy pathway.
chaperone-mediated autophagy (CMA). In this neurodegenerative conditions should follow. In worms and mice, these drugs increase
S16 | Nature | Vol 601 | 20 January 2022
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flowing through the autophagy pathway. As
Casma’s chief scientific officer, Leon Murphy,
explains: “We’re essentially educating the
autophagy pathway to go after a disease target
and to eliminate that from the diseased cell.”
Research teams from Tohoku University
in Sendai, Japan, and Fudan University in
Shanghai, China, first described this approach
in 2019, each detailing a different way to
design compounds that escort target mol-
ecules to phagophores for demolition. The
Tohoku team made a mitochondria-targeting
degrader10, whereas the Fudan group made
DON W. FAWCETT/SCIENCE PHOTO LIBRARY
a selective degrader of mutant huntingtin
proteins11 — a strategy now being pursued by
PAQ Therapeutics, a Fudan University spin-off
company in Cambridge, Massachusetts.
Researchers who have long studied auto-
phagy but found little industry interest wel-
come the attention that drug companies are
finally paying to the field. Some think the
power of autophagy could be harnessed in
A colour-enhanced transmission electron micrograph of an autophagic vacuole. any number of different ways — including with
creative dosing strategies to maximize the
lifespan and overall well-being. But because cells to tens of thousands of drug compounds therapeutic effect. “Maybe you want to use it
they have many molecular effects, “you can and then running assays designed to detect periodically instead of chronically to avoid the
never be sure what is due to autophagy,” any changes in autophagy function. This negative effects of too high autophagy,” says
says Beat Nyfeler, a chemical biologist at the work has yielded three promising drug leads, Congcong He, a cell biologist at Northwestern
Novartis Institutes for BioMedical Research in Hamley says, which the team is now trying to University’s Feinberg School of Medicine in
Basel, Switzerland. validate. Chicago, Illinois. The mice used in Sebti’s land-
Unfortunately, the molecular promiscuity Some companies are taking a more target- mark 2018 study were created by He, who has
of mTOR signalling, which also controls pro- focused approach. At Caraway Therapeutics unpublished data validating this ‘less is more’
tein synthesis, and the nonspecific nature of in Cambridge, Massachusetts, president and approach to autophagy induction.
the drugs can also result in unwanted side chief scientific officer Magdalene Moran uses There could also be synergies between dif-
effects. “I think to really address the power of human genetics to guide her team’s drug ferent parts of the process. “It may be valuable
activating autophagy one would need to find discovery. Mutations in several lysosome- to both turn on the degradative process itself,
something mTOR-independent,” Nyfeler says. associated proteins are known to cause devas- and then also to enhance the delivery of a cer-
By repurposing an existing drug, David tating neurodegenerative disease, so Moran tain substrate into the autophagosome,” says
Rubinsztein, a cellular neurobiologist at the and her colleagues reasoned that promoting Skip Virgin, a scientific co-founder of Casma
University of Cambridge, UK, has identified a the function of those same proteins could have who now leads research efforts at Vir Biotech-
blood-pressure medication that induces auto- therapeutic benefit. “What we’re really looking nology, an immunotherapies company in San
phagy through other means. Called felodipine, to do is enhance the capacity of these existing Francisco, California, that is also studying
it works by blocking calcium channels, both pathways to address disease,” she says. autophagy.
to relax blood vessels — hence its use to treat This would be like putting more garbage
hypertension — and to increase autophagic “We’re essentially educating trucks on the road and increasing the size of
activity. trash incinerators to ensure clean and safe
In mouse models of Parkinson’s and
the autophagy pathway to streets. Along the road to ageing, cells might
Huntington’s disease, Rubinsztein and his col- go after a disease target.” benefit from similar investment in waste
leagues have shown that the drug promotes management.
the clearance of aggregate-prone proteins
from the brain, resulting in behavioural and Casma Therapeutics, also in Cambridge, Elie Dolgin is a science journalist in
functional improvements9. A clinical trial is Massachusetts, has its sights set on a few spe- Somerville, Massachusetts.
now planned to evaluate whether felodipine cific targets that would rev up autophagy in
1. Fernández, Á. F. et al. Nature 558, 136–140 (2018).
treatment can reduce levels of mutant hun- cells for which the decomposition system is 2. Wang, C. et al. Autophagy 8, 1–14 (2021).
tingtin protein in the spinal fluid of people with impaired. But the company — which Levine 3. Rocchi, A. et al. PLoS Genet. 13, e1006962 (2017).
4. Shi, M. et al. FASEB J. 34, 3129–3150 (2020).
early-stage Huntington’s disease. helped to found with Andrea Ballabio, sci- 5. Anguiano, J. et al. Nature Chem. Biol. 9, 374–382 (2013).
Other companies, meanwhile, are looking entific director of the Telethon Institute of 6. Bourdenx, M. et al. Cell 184, 2696–2714 (2021).
7. Dong, S. et al. Nature 591, 117–123 (2021).
to develop selective autophagy-activating Genetics and Medicine in Naples, Italy, and 8. Xie, C. et al. Nature Biomed. Eng. https://doi.org/10.1038/
agents directed at different therapeutic tar- others — is advancing a platform technology s41551-021-00819-5 (2022).
9. Siddiqi, F. H. et al. Nature Commun. 10, 1817 (2019).
gets. At Samsara Therapeutics, scientists have that would target any troublesome cellular 10. Takahashi, D. et al. Mol. Cell 76, 797–810 (2019).
approached the problem by exposing cultured component and send the unwanted material 11. Li, Z. et al. Nature 575, 203–209 (2019).
Nature | Vol 601 | 20 January 2022 | S17
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