so say specialists irina and mike conboy
FILTERING OUR AGED BLOOD CAN MAKE US YOUNG
interview by
STEVE HILL & NICOLA BAGALA
___________________________________________________________________
Due
to a recently published study on the effects of young plasma
on aged mice, we got in touch with Dr. Irina Conboy of Berkeley
University. Dr. Conboy is an Associate Professor at the Department
of Bioengineering and an expert in stem cell niche engineering,
tissue repair, stem cell aging and rejuvenation. Before we dive
into the main topic, let’s familiarize ourselves a little
with Dr. Conboy and her work.
Dr.
Conboy got her Ph.D. at Stanford University, focusing on autoimmunity.
She met her partner in science—and in life—Dr. Michael
Conboy at Harvard and they got married before embarking on graduate
studies; they celebrated their Silver Anniversary a few years
ago. During her postdoctoral studies, she began focusing on
muscle stem cells, trying to figure out what directs them to
make new healthy tissue and what causes them to lose their ability
to regenerate the tissues they reside in as we age.
Together
with her husband Michael, she eventually discovered that old
stem cells could be reactivated and made to behave like young
ones if appropriately stimulated. The Conboys’ parabiosis
experiments—which consisted in hooking up the circulatory
systems of aged and young mice—showed that old age is
not set in stone and can be reversed in a matter of weeks.
The
follow-up work by the Conboys uncovered that age-accumulated
proteins, such as TGF-ß1, inhibited stem cells’
ability to repair tissues even in young mice, and when TGF-ß1
signaling is normalized to its young levels, old mice (equivalent
to 80-year old people) have youthful muscle regeneration and
better neurogenesis in the hippocampus (the area of the brain
that is responsible for memory and learning).
While
young blood did appear to be beneficial to old stem cells, their
evidence suggested that the real culprit of the broad loss of
tissue repair with age was the negative influence of age-accumulated
inhibitory proteins in aged tissues and circulation, also called
the stem cell niche.
This
conclusion is certainly compatible with the view of aging as
a damage accumulation process. As Irina herself pointed out
in this interview, in the parabiosis experiments, the old mice
had access to the more efficient young organs: lungs, liver,
kidneys and immune system of the younger mice, which likely
accounted for many of the benefits observed in the elderly parabiosed
mice. With respect to the rejuvenation of the brain, the old
mice experienced environmental enrichment by being sutured to
young, more active parabionts, and this is known to improve
the formation of new brain cells, learning, and memory.
An
aged niche blocks the action of old and young stem cells alike
very quickly; therefore, as Dr. Conboy observed in an article
in the Journal of Cell Biology, we can’t treat the diseases
of aging by simply transplanting more stem cells, because they
will just stop working. Their niche needs to be appropriately
engineered as well. Fortunately, there are potential solutions
to this problem; such as the use of artificial gel niches and
defined pharmacology that are designed to protect transplanted
or endogenous stem cells from the deleterious environment of
the old body.
This
research holds the potential to significantly postpone the onset
of age-related diseases and possibly reverse them one day, including
frailty, muscle wasting, cognitive decline, liver adiposity
and metabolic failure, but Dr. Conboy remains cautious about
the possibilities until more data is in. However, she does think
that longer and healthier productive lives could improve people’s
attitudes towards the environment and treating each other with
compassion and respect—a view that we definitely share.
We
managed to catch up with Irina and Michael Conboy and talk to
them about their work.
STEVE
HILL & NICOLA BAGALA: For the sake of those new to the topic,
what is it in young blood and aged blood that affects aging?
DR. IRINA
CONBOY: Numerous changes in the levels of proteins that together
regulate cell and tissue metabolism throughout the body.
DR. MIKE
CONBOY: We wondered why almost every tissue and organ in the body
age together and at a similar rate, and from the parabiosis and
blood exchange work now think that young blood has several positive
factors, and old blood accumulates several negative, “pro-aging”
factors.
SH &
NB: A lot of media attention and funding is currently being directed
to youthful blood transfusions; how can we move beyond this to
potentially more promising approaches, such as filtering and calibration
of aged blood?
DR. IRINA
CONBOY: People need to understand not just the titles, abstracts
and popular highlights of research papers, but the results and
whether they support (or not) the promise of rejuvenation by young
blood. In contrast to vampire stories, we have no strong experimental
evidence that this is true, and there is a lot of evidence that
infusing your body with someone else’s blood has severe
side effects (even if it is cell-free).
DR. MIKE
CONBOY: Translational research.
SH &
NB: Some evidence suggests dilution is the most likely reason
that young blood has some beneficial effects; what are your thoughts
on this recent study in rats that shows improved hepatic function
partially via the restoration of autophagy?
DR. IRINA
CONBOY: There are certainly “young” blood factors
that are beneficial, not just a dilution of the old blood, and
this benefit differs from organ to organ. We have published on
improved liver regeneration, reduced fibrosis and adiposity by
transfusion of old mice with young blood, but these are genetically
matched animals, and in people, we do not have our own identical
but much younger twins.
SH &
NB: If dilution is also playing a role here, then can we expect
similar or better results from calibrating aged blood?
DR. IRINA
CONBOY: Yes, and our work in progress supports the idea.
SH &
NB: In your 2015 paper, you identified that TGF-ß1 can be
either pro-youthful or pro-aging in nature, depending on its level.
In the study, you periodically used an Alk-5 inhibitor to reduce
TGF-ß1 levels and promote regeneration in various tissues.
In the study, you showed that TGF-ß1 was important in myogenesis
and neurogenesis; is there reason to believe that this mechanism
might be ubiquitous in all tissues?
DR. IRINA
CONBOY: Yes, because TGF-ß1 receptors are present in most
cells and tissues.
SH &
NB: Also, TGF-ß1 is only one of a number of factors that
need to be carefully balanced in order to create a pro-youthful
signalling environment. How many factors do you believe we will
need to calibrate?
DR. IRINA
CONBOY: There will be a certain benefit from calibrating just
TGF-beta 1, but also additional benefits from more than one or
just TGF-beta.
SH &
NB: How do you propose to balance this cocktail of factors in
aged blood to promote a youthful tissue environment?
DR. IRINA
CONBOY: We are working on the NextGen blood apheresis devices
to accomplish this.
SH &
NB: So, you are adapting the plasmapheresis process to effectively
“scrub” aged blood clean and then return it to the
patient. This would remove the need to transfuse blood from young
people, as your own blood could be filtered and returned to you,
and no immune reaction either, right?
DR. IRINA
CONBOY: Accurate.
SH &
NB: This plasmapheresis technique is already approved by the FDA,
we believe, so this should help you to develop your project faster,
right?
DR. IRINA
CONBOY: Exactly.
SH &
NB: Do you think a small molecule approach is a viable and, more
importantly, a logistically practical approach to calibrate all
these factors compared to filtering aged blood?
DR. IRINA
CONBOY: Yes, it is a very feasible alternative to the NextGen
apheresis that we are working and publishing on.
SH &
NB: It is thought that altered signaling is caused by other aging
hallmarks higher up in the chain of events; even if we can “scrub”
aged blood clean, is it likely to have a long-lasting effect,
or would the factors reach pro-aging levels fairly quickly again
if nothing is done about the other hallmarks antagonizing them?
DR. IRINA
CONBOY: That needs to be established experimentally, but due to
the many feedback loops at the levels of proteins, genes and epigenetics,
the acquired youthful state might persist.
SH &
NB: Ultimately, could a wearable or an implanted device that constantly
filters the blood be the solution to these quickly accumulating
factors?
DR. IRINA
CONBOY: Maybe, but the first step of a day at a NextGen apheresis
clinic once every few months might be more realistic.
SH & NB: Filtering seems to be a far more practical solution,
so how are you progressing on the road to clinical trials?
DR. IRINA
CONBOY: We are collaborating with Dr. Dobri Kiprov, who is a practicing
blood apheresis physician with 35 years of experience, and he
is interested in repositioning this treatment for alleviating
age-related illnesses.
SH &
NB: Senolytics and removing senescent cells and the resulting
inflammation they cause during the aging process has become a
hot topic in the last year or so. What are your thoughts on senolytics
as a potential co-therapy with a blood filtering approach?
DR. IRINA
CONBOY: Might be good, but we should be careful, as p16 is a normal,
good gene that is needed for many productive activities by many
cells.
SH &
NB: What do you think it will take for the government to fully
support the push to develop rejuvenation biotechnology?
DR. IRINA
CONBOY: Clear understanding of the current progress and separating
the real science from snake oil is very important for guiding
funding toward realistic clinical translation and away from the
myth and hype.
SH &
NB: The field is making amazing progress, but, sadly, it is plagued
by snake oil. As much as an “anti-aging free market”
encourages innovation, it also encourages hucksters. How can a
member of the public tell the difference between credible science
and snake oil?
DR. IRINA
CONBOY: I was thinking for some time about starting a popularized
journal club webpage where ordinary people can see what we typically
critically point out in the lab setting about published papers
and clinical trials.
SH &
NB: How can our readers learn more about your work and support
your research?
DR. IRINA
CONBOY: The new Conboy lab website is coming up; meanwhile, contact
me and Dr. Mike at iconboy@berkeley.edu and conboymj@berkeley.edu
CONCLUSION
We would like to thank Irina and Michael for taking the time to
answer our questions and for providing the readers with a fascinating
insight into their work.
