Researchers, publishing in Nature, have reported that a mutation in a protein involved in autophagy – the process of breaking down cellular components into their constituent parts to be recycled – leads to extended lifespan and improved health in mice.
Prof Lynne Cox, Associate Professor of Biochemistry, University of Oxford, said:
“Ageing is a complex biological process. Studies such as this one in genetically engineered mice are important in starting to untangle what happens at the molecular level, with the hope that such understanding will allow development of new drugs or other treatments for age-related diseases including heart and kidney disease and cancer.
“This study takes a further step along the way to understanding and correcting part of the molecular problem in ageing. The scientists genetically engineered mice to produce a more active form of a protein called Beclin, allowing cells to break down damaged cellular components or those surplus to requirements more effectively than usual. It has been known for some time that a failure of this process of breakdown, or autophagy (literally, ‘self-eating’), may contribute to frailty and diseases of ageing (including some forms of dementia), and the findings reported build on earlier research, showing increases in lifespan and health in older mice. The study also hints towards novel treatment approaches.
“New advances: Excitingly, this study showed increased lifespan accompanied by a reduction in age-related detrimental changes to the heart and kidneys, together with lower incidence of age-related cancers, in otherwise normal older mice that make a more active form of Beclin.
The study also found that the active Beclin protected prematurely ageing mice from early death. The correction of this premature ageing provides new clues as to how an important anti-ageing protein works.
“Comments on validity of the work: The press release is essentially accurate in that it places the work in the context of earlier studies and does not over-hype the current research.
The experiments are conducted using adequate numbers of experimental animals to provide sensible conclusions, and the techniques used are appropriate to address the questions asked.
The new work fits closely with what we already know about the role of autophagy in ageing, and the importance of Beclin 1-Bcl2 interaction – it represents a step further, not a giant leap, but it does suggest that the anti-ageing protein Klotho might act to disrupt this interaction and therefore that drug design should be focussed on breaking the association between Beclin 1 and its negative regulator Bcl2.
“Limitations: Some caution is still needed: though this study looked at liver, heart, kidney and muscle, it did not assess the effect on all tissues and brain is a notable omission, presumably because the same authors have already published on the effects of this Beclin mutation in an Alzheimer’s model in mice. The treatment actually restored fertility to the prematurely ageing mice, but the effect on normal mice should also be assessed to make sure that gains in later life health are not at the cost of fertility. In terms of extending these findings to future drug discovery, it is important to remember that too much autophagy is as bad as too little. Drugs that disrupt interactions between important cellular proteins may not have the same effects as the natural control mechanisms and obtaining the correct level of autophagy will be important
“Real world applications: Being able to delay or even prevent the onset of age-related disease, as reported here, has enormous potential to improve the quality of later life in people, and this study takes us a step further towards understanding what drives age-related diseases and how we might be able to intervene. It must be cautioned that the current study is simply a proof of concept and uses genetically engineered mice; while the techniques are not directly applicable to humans, the core principles are likely to apply as the underlying biochemistry is highly conserved between mice and humans. Notably, the study does test a way of controlling autophagy using a soluble anti-ageing protein, a finding which will be important in designing drugs that may be able to delay the onset of age-related diseases through promoting autophagy.”
Prof Dorothy Bennett, Director of the Molecular and Clinical Sciences Research Institute, St George’s, University of London, said:
“This is careful and high-quality research. The conclusions in the press release seem to be clearly supported by the data, which also fit with a good deal of previous research from the same and different groups, implicating decline in autophagy as potentially a central mechanism in ageing.
“All these data come from mice and mouse cells, so extrapolation to humans would be speculative; they do use terms like “longevity in mammals” based on this one mammal, but (correctly) no specific conclusions about other mammals are drawn.
“An interesting point is about the use of the protein klotho. It has previously been reported that mice genetically deficient in klotho die prematurely, but treatment of these mice with soluble klotho restored lifespan, increased autophagy as measured in the kidney, and reduced renal disease. In the present study, soluble klotho reduced beclin 1 interaction with its inhibitor BCL2 (so klotho should increase beclin 1 activity). Turning to the activating beclin 1 mutation studied here: klotho-deficient mice bred to have also this beclin 1 mutation were cured of their premature death, indicating that klotho may act through beclin 1.
“The point there is that a soluble substance administered to mice – at least mice that die young – can increase their lifespan, with some evidence of a mechanism of action (increased beclin 1 activity) that so far appears to be safe and even to reduce the incidence of tumours. It will be very interesting to see in future research how and whether these effects may be applicable to normal mice and to humans.”
Dr Hanlin Zhang, Postdoctoral Researcher in Autophagy and Immune senescence, Kennedy Institute of Rheumatology, University of Oxford, said:
“Autophagy has long been considered as an anti-ageing mechanism, and multiple autophagy-inducing interventions such as caloric restriction (in model organisms and mammals including humans) and the autophagy inducer spermidine treatment (in mice and lower model organisms) have been shown to delay ageing. However, direct evidence of specific induction of autophagy by genetic modulations is still limited in the mammalian system (except a pioneering study by Pyo et al. showing that overexpression of the key structural autophagy protein Atg5 induces autophagy and extends mice lifespan).
“Here Fernandez et al. use an elegant knock-in mouse model with a single point mutation in the upstream signaling autophagy molecule beclin 1 to induce autophagy and show that both life span and to a certain extent health span in multiple organs are prolonged. The discovery strongly supports the idea that inducing autophagy serves as an effective way to delay mammalian ageing, and beclin 1 is a realistic target.
“One limitation of this study is that more functional tests could have been done to properly assess the anti-ageing improvements.
“The klotho rescue data is especially novel and striking. However it is not fully investigated if the rescue by beclin 1 point mutation works via autophagy induction (only endocytosis with a known link with ageing was excluded).
“Further questions still remain how autophagy changes with age in different organs and if beclin 1 contributes to such changes. It is interesting to next investigate if genetic induction of autophagy during mid-to-late life will have similar anti-ageing effects, and critically if drugs targeting beclin 1, such as Tat-beclin 1, that the Levine group has previously developed, can delay ageing. It is also possible that targeting alternative steps of autophagy or other ageing signaling pathways may have a synergistic effect on delaying ageing while inducing beclin 1 activity.”
Dr David Clancy, Lecturer in the Department of Biomedical & Life Sciences, Lancaster University, said:
“Levine, Hu and colleagues have produced excellent, well controlled and comprehensive mouse data showing that a well studied candidate for lifespan modulation – autophagy – can achieve a 12% increase in lifespan in both male and female mice.
“Using a gain-of-function mutation, autophagy was increased, onset of population ageing was delayed increasing average and maximum lifespan, and typical age-related pathologies were reduced. Other indices of functional health such as cognitive function, reproductivity, activity and sleep were not measured, so we do not know if there were any trade-offs involved.
“This paper suggests mechanistic evidence for the average 4.7 years of extra healthy life in humans afforded by the best known inducer of autophagy i.e. exercise. While exercise has many other benefits, the lifespan effect might be achieved pharmacologically in the future although, as this study only looks at mice, further research must be done in humans to demonstrate if this may be possible.”
Prof Ilaria Bellantuono, Professor of Musculoskeletal Ageing, University of Sheffield, said:
“This work is scientifically important because it complements previous work and shows that increasing autophagy delays some of the signs of ageing. It builds our knowledge to show that by interfering with mechanisms of ageing it is possible to improve some parameters of health. This knowledge is useful to encourage the development of new drugs to prevent multiple diseases to keep us healthier for longer.
“In this study there is a thorough assessment of the improvement in autophagy in the mice following genetic modification and it shows how the genetic modification reverse the age-related decline in autophagy only in part. However, there is much more work to do to understand whether this discovery can improve health in people. Whilst it is clear that, the increase in autophagy, results in an extension in survival, this may be due to reduced incidence of cancer rather than to an overall improvement in health. The assessment of the effect on health is limited to changes in the structure of the heart and kidney. There is no assessment of whether those changes results in improved function of these two important organs. In addition, there are other important functions, which are lost with age and impact on our health and quality of life such as cognition and memory, mobility and coordination, immunity (ability to respond to infections), ability to metabolise glucose appropriately. Unfortunately, this study does not assess these functions.”
Dr Nicholas Ktistakis, Research group leader, Babraham Institute, said:
“Autophagy is a process that occurs in cells, breaking down no longer useful cell components into their constituent molecules to be reused. This study looked at the protein beclin1 which is involved in this process.
“The press release accurately reflects the science. The research is of very high quality: multiple lines of inquiry are presented, and mechanistic detail of the observed phenotypes has been established.
“In order to enhance autophagy, the authors have generated a mutated form of the beclin 1 protein that reduces binding to BCL-2, an important protein that on its own promotes cell survival. Previous evidence has suggested that functional autophagy is required for many different genetic and pharmacological manipulations that extend lifespan. But what has been less clear is whether enhanced autophagy on its own can improve lifespan, with only one previous paper addressing this in detail. This paper provides evidence that this is the case.
“The effects on longevity seen in mice are modest, and enhanced autophagy appears to only partially protect against known ageing defects. In this way, the safest interpretation from this work, as made clear by the authors, is that autophagy can be a contributing factor to healthy ageing.
“Although the authors try to address this point, it is possible that not all of the effects seen are via Beclin1, but they may be via BCL-2.”
* ‘Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice’ by Álvaro Fernández et al. was published in Nature on Wednesday 30th May.
All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/ageing/
Prof Lynne Cox:
Paid employment: Associate Professor of Biochemistry at the University of Oxford and Tutorial Fellow in Biochemistry at Oriel College, Oxford
Grant funding: BBSRC, Amway, private donor through the University of Oxford Development office, MRC (all to work on ageing projects)
Voluntary appointment: Trustee of the British Society for Research on Ageing
Prof Dorothy Bennett: No declarations of interest
Dr Hanlin Zhang: Postdoc is funded by Elysium Health
Dr David Clancy: No competing interests to declare
Prof Ilaria Bellantuono: “I have funding from MRC Arthritis Research UK, Horizon 2020, Cancer Research UK, and BBSRC, and I am chair of the BBSRC Bioscience skills and career strategy panel, and NC3Rs studentship panel.”
Dr Nicholas Ktistakis: No declarations of interest