[Valter]: We always prefer to go with where we have human evidence, then there are no
consequences and there's a growth hormone receptor, right?
[Rhonda]: Mm-hmm.
[Valter]: So, we're not developing drugs against growth hormone receptor, why?
Because we have the Ecuadorean that we've been following for 10 years, and Guevara,
our colleagues, has been following them for 30 years.
And that's fine, they make it to very old age.
[Rhonda]: In years by now, so people like, you know, the IGF-1, and growth hormone pathway...
[Valter]: Right.
So, essentially, proteins and amino acids control two major pathways, right?
One is the growth hormone IGF-1, which is called an axis, it's not really a pathway,
but an axis.
And then, the other one is tyrosine kinase, right?
So, if you have a lot of amino acids, those two are activated, and both are now widely
recognized, it's very powerful pro-aging pathways.
And so, yeah, of course, you could do it by food, or you could do it by mutations.
So, if you take a mouse and you knock out the growth hormone receptor, this mouse will
live 40%, 50% longer.
It's also, and in spite, and this is work by John Kopchick and Andre Barkey, and in
spite of living longer, it has much less diseases.
So, almost half of these mice will get to the end of life with no diseases that are
visible, right?
So, it's really remarkable.
And as remarkable, I think, is our work with humans that have the same mutation in the
growth of more receptor, and these people will live, maybe, a little bit longer.
Not 40% longer, for sure, but they have a terrible diet, they smoke, they drink, they
really don't watch anything they do.
And in spite of all this, they almost never get cancer, they almost never get diabetes,
we really haven't seen any chronic disease in these people, in the same household like
a normal diseases, right?
So, it's nothing to do with Ecuador, it has to do with mutation.
[Rhonda]: Mm-hmm.
[Valter]: Which matches very well with the mouse data.
So, yeah, I think that that is a much better target.
I mean, I'm biased, but I think having all of it available to us for a long time, and
we picked the target that was the least likely to cause any side effects also based on, you
know, very long-term human data.
[Rhonda]: There's also human data showing that there's polymorphisms in, for example,
the IGF-1 receptor, or that whole pathway, you know, that are also consistent with longevity
as well.
[Valter]: Yeah, yeah.
FOXO that are in communication and polymorphism.
And FOXO in the IGF-1 receptor, in the growth hormone receptor, yeah.
[Rhonda]: Right.
It's all consistent, where, I mean...
[Valter]: I think so, yeah.
[Rhonda]: I remember, in fact, one of my first experiments in biology was doing, you know,
manipulating the IGF-1 signaling pathway in worms, in Andrew Dillin's lab at the Salk
Institute.
And I remember when I saw, you know, when you get rid of that pathway in these worms,
they live 100% longer.
I mean, it was like amazing to me that you could change one genetic pathway and cause
a worm to live like 100% longer.
I mean, that, to me, was mind-blowing.
Like how is that...and these are genes that are conserved in humans, nonetheless, so it
really makes you think, "Well, if this can happen to a worm, you know, what's the potential
for humans?"
And we know, centenarians have like, you said, FOXOs.
So IGF-1 just for people, so that IGF-1 is a growth signaling pathway that...I don't,
and maybe you can answer this question for me.
When I think about it, for human aging, I always think about too much IGF-1 playing
an important role in cancer, promoting cancer growth.
When I was studying it in worms, it was more about not inhibiting this very important stress
response pathway, the FOXO3 pathway, and how that's important for turning on all these
genes that are involved in stem cell, making stem cells, and autophagy, and degrading proteins.
And it's just like a master regulator of all these, like, amazing genes that can help you
if you smoke, or just help you deal with the stresses of aging in general.
For humans, do you think that lowering IGF-1 is going to have a more profound effect on
human lifespan via, like, not getting cancer, or do you think not inhibiting that FOXO3
pathway is just as important?
[Valter]: Probably it's very much connected, meaning that the aging process is the driver
for the cancer, about to the level of a cancer cells and accumulation of mutation, but also
the level the tissues getting more inflammation, be more permissive to the metastasis, and
also the level of the immunosenescence, and the immune system getting weaker.
And we know that if you have an immune deficient mouse, the cancer grows a lot faster.
So, yeah, so then, the aging process is really anything most of us agree, the primary driver
of the age-related disease, which is cancer, and, of course, all the other age-related
diseases.
So, yeah, so we're always looking in terms of, you know, treat aging, and then the rest
comes.
Now, of course, yeah, there are all the things that might not be necessarily related to aging.
For example, if you have a high IGF-1 in the moment where the cancer cell is generated,
that cancer cell might still love to have a lot of IGF-1 because it helps prevent apoptosis.
And so, yeah, there could be a dual role of some of these growth factors in making sure
that the cancer becomes a metastatic cancer, that some of it maybe an independent of the
aging process.