Aging in human cells successfully reversed in the lab
Scientists reversed the ageing of human cells, which could provide the basis for future anti-degeneration drugs.
The ability to reverse aging is something many people would hope to see in their lifetime. This is still a long way from reality, but in our latest experiment, we have reversed the aging of human cells, which could provide the basis for future anti-degeneration drugs.
Aging can be viewed as the progressive decline in bodily function and is linked with most of the common chronic diseases that humans suffer from, such as cancer, diabetes and dementia. There are many reasons why our cells and tissues stop functioning, but a new focus in the biology of aging is the accumulation of “senescent” cells in the tissues and organs.
Senescent cells are older deteriorated cells that do not function as they should, but also compromise the function of cells around them. Removal of these old dysfunctional cells has been shown to improve many features of aging in animals such as the delayed onset of cataracts.
We still don’t fully understand why cells become senescent as we age, but damage to DNA, exposure to inflammation and damage to the protective molecules at the end of the chromosomes – the telomeres – have all been suggested.
More recently, people have suggested that one driver of senescence may be loss of our ability to turn genes on and off at the right time and in the right place.
One gene, many messages
As we age, we lose our ability to control how our genes are regulated. Each cell in the body contains all the information needed for life, but not all genes are switched on in all tissues or under all conditions. This is one of the ways that a heart cell is different from a kidney cell, despite the fact they contain the same genes.
When a gene is activated by signals from inside or outside the cell, it makes a molecular message (called an RNA) that contains all the information needed to make whatever that gene makes. We now know that over 95% of our genes can actually make several different types of messages, depending on the needs of the cell.
A good way to think about this is to consider each gene as a recipe. You could make either a vanilla sponge, or a chocolate cake, depending on whether you include the chocolate. Our genes can work like this. The decision as to which type of message is produced at any given time is made by a group of about 300 proteins called “splicing factors”.
As we age, the amount of splicing factors we are able to make declines. This means that aged cells are less able to switch genes on and off to respond to changes in their environment. We and others have shown that the levels of these important regulators decline in blood samples from elderly humans, and also in isolated human senescent cells of different tissue types.
Rejuvenating old cells
We have been looking for ways to turn the splicing factors back on. In our new work, we showed that by treating old cells with a chemical that releases small amounts of hydrogen sulphide, we were able to increase levels of some splicing factors, and to rejuvenate old human cells.
Hydrogen sulphide is a molecule that is found naturally in our bodies and has been shown to improve several features of age-related disease in animals. But it can be toxic in large amounts, so we needed to find a way to deliver it directly to the part of the cell where it is needed.
By using a “molecular postcode” we have been able to deliver the molecule directly to the mitochondria, the structures that produce energy in cells, where we think it acts, allowing us to use tiny doses, which are less likely to cause side effects.
We are hopeful that in using molecular tools such as this, we will be able to eventually remove senescent cells in living people, which may allow us to target multiple age-related diseases at once. This is some way in the future yet, but it’s an exciting start.
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Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.
- Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
- They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
- The research raises many ethical questions and puts to the test our current understanding of death.
The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?
But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.
What's dead may never die, it seems
The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.
BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.
The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.
As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.
The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.
"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.
An ethical gray matter
Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.
The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.
Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.
Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?
"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."
One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.
The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.
"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.
It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.
Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?
The dilemma is unprecedented.
Setting new boundaries
Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."
She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.
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