Of Bones & Bel­lies A game-chang­ing break­through on one wily hor­mone

Could one wily hor­mone be the hav­ocin­duc­ing neme­sis of mid-life health?

ZOOMER Magazine - - CONTENTS MARCH 2018 - By Carolyn Abra­ham

RESEARCHERSINTHE UNITED STATES are gear­ing up for an ex­per­i­ment in hu­mans which, if it suc­ceeds, could one day change ev­ery­thing about ag­ing. Well, if not ev­ery­thing, cer­tainly a lot of things: imag­ine if grow­ing older no longer meant los­ing en­ergy, strong bones and your waist­line.

The ex­per­i­ment, based on a star­tling dis­cov­ery re­cently made in mice, is aimed at solv­ing some of mid-life’s most vex­ing prob­lems – and with just one ther­apy.

It’s no won­der the web is abuzz with peo­ple ea­ger to vol­un­teer for the test­ing. As the blog­ger be­hind Ag­ing Grace­fully My Ass put it: “Pick me! Pick me!”

The con­cept for the ther­apy grew out of re­search re­lated to menopause when sci­en­tists dis­cov­ered a sin­gle un­ex­pected hor­mone seems to play a pri­mary role for both thin­ning bones and ex­tra ab­dom­i­nal fat that be­gins to haunt women in mid-life.

De­clin­ing es­tro­gen had al­ways been con­sid­ered the chief vil­lain be­hind th­ese menopausal scourges, which raise the risk of frac­tures, di­a­betes and cer­tain can­cers. But the re­search, repli­cated in two sep­a­rate labs over a two-year stretch, pins the blame on high lev­els of a fol­li­cles­tim­u­lat­ing hor­mone (FSH), a

lesser-known re­pro­duc­tive hor­mone found in both women and men.

What’s more, in mice, block­ing FSH not only slowed bone loss, it had the sur­pris­ing side-ef­fect of also boost­ing weight loss, me­tab­o­lism and phys­i­cal ac­tiv­ity in the males and fe­males. Specif­i­cally, it coun­tered the mid-life weight re­dis­tri­bu­tion that tends to add stub­born pounds around the stom­ach.

The re­sults, pub­lished last year in Na­ture, were so tan­ta­liz­ing that, although the work was con­ducted in an­i­mals, it gar­nered cov­er­age in both the New Eng­land Jour­nal of Medicine and the New York Times. Af­ter all, if FSH works the same way in hu­mans, it could yield a new way to com­bat obe­sity and os­teo­poro­sis, two of the fastest grow­ing is­sues for hu­man health.

“The fas­ci­nat­ing part is that it’s not only ap­pli­ca­ble to women,” said lead re­searcher Dr. Mone Zaidi, di­rec­tor of the Mount Si­nai Bone Pro­gram in New York. “If you look at the mouse data, it hap­pens in male mice as well, so this could be broadly ap­pli­ca­ble to both sexes and all ages.”

Zaidi, whose work now has en­thu­si­as­tic fol­low­ers in the bl­o­go­sphere, said he is “cau­tiously op­ti­mistic” that the treat­ment will trans­late into hu­mans, in part be­cause of the “mag­ni­tude of the ef­fects” ob­served in mice given the FSH blocker.

“It’s not like you are see­ing a 15 or a 20 per cent change in body fat, you are see­ing a 50 per cent change with the an­ti­body. I mean, this is huge.”

As far as hor­mones go, FSH has never re­ally had a sexy role in the pop­u­lar psy­che. Next to es­tro­gen, it’s been a mousey un­der­study. It lacks testos­terone’s swag­ger, and even its acro­nym hides a dowdy han­dle: FSH stands for fol­li­cle-stim­u­lat­ing hor­mone. In men, it helps to make sperm and in women, its lev­els spike to trig­ger ovu­la­tion, coax­ing the ovar­ian fol­li­cles to re­lease eggs.

“When we think of FSH, clas­si­cally, we think of it as the hor­mone that drives ovar­ian func­tion,” said Dr. Jen­nifer Blake, CEO of the So­ci­ety of Ob­ste­tri­cians and Gy­nae­col­o­gists of Canada. “More of­ten, it’s a marker (doc­tor’s test) that can re­as­sure women in their re­pro­duc­tive years.

“The ma­jor thing here is that it’s quite in­ter­est­ing that [FSH] does other things in the body.”

In fact, be­yond fer­til­ity, FSH had not been con­sid­ered a ma­jor player in menopause or me­tab­o­lism. Zaidi, how­ever, who is also a pro­fes­sor of medicine and en­docrinol­ogy at Mount Si­nai’s Ic­ahn School of Medicine, has a track record for ques­tion­ing the tra­di­tional.

For years, he’s in­ves­ti­gated what the text­books don’t say about the se­cret life of hor­mones. It’s a mis­sion that stems from his in­ter­est in dis­eases that ac­com­pany menopause, par­tic­u­larly os­teo­poro­sis, which leaves about two in ev­ery five women with frag­ile bones by age 70.

From his clin­i­cal work treat­ing women with HRT, Zaidi knew that es­tro­gen could have “fairly pro­found ef­fects in pro­tect­ing against bone loss.” But he set out to see if other hor­mones from the pi­tu­itary gland, that pea-sized master gland at the base of the brain, might also af­fect bone, which, at the time, was heresy.

Stan­dard phys­i­ol­ogy text­books, most of them com­piled in the early half of the 20th cen­tury, tend to type­cast hor­mones, de­pict­ing them as chem­i­cal mes­sen­gers that float through the blood­stream to­ward a sin­gle tar­get and no other. Even their names im­ply it.

“The way hor­mones have been named, and we need to change th­ese names now, is that thy­roid-stim­u­lat­ing hor­mone acts on the thy­roid gland to make thy­roid hor­mones; fol­li­cle-stim­u­lat­ing hor­mone acts on the ovar­ian fol­li­cles …. Cor­ti­cotropic hor­mone … acts on the adrenals to make more cor­ti­sol.” The trou­ble is the names have lim­ited the way sci­en­tists think about what else th­ese hor­mones might do, Zaidi said.

Yet in 2001, Zaidi showed that that thy­roid-stim­u­lat­ing hor­mone works not only on the thy­roid gland but also that it can by­pass the gland to work di­rectly on bone. He found that bones carry spe­cific re­cep­tors, which, like molec­u­lar key­holes, FSH can un­lock.

“Then that led to this sort of hunch that other hor­mones may be do­ing the same thing.” Sure enough, in 2006, Zaidi showed that bone also has re­cep­tors for the fol­li­cle-stim­u­lat­ing hor­mone and that FSH works di­rectly on bone, not just the ovaries.

To Zaidi, the find­ings sug­gested high FSH might be a cul­prit in midlife bone loss, since it was well known FSH lev­els rise at menopause as the brain sends out more and more in an ap­par­ent ef­fort to force the ovaries to re­spond while es­tro­gen lev­els fall. But, to oth­ers, that sug­ges­tion was con­tro­ver­sial.

“There was big push­back from the bone com­mu­nity,” Zaidi re­called, “par­tic­u­larly the es­tro­gen folks who said, ‘You can’t be right be­cause es­tro­gen is the ma­jor hor­mone that goes down…. FSH re­ally has noth­ing to do with bone.’

“I said, ‘No, FSH prob­a­bly does have a lot to do with bone. That’s the ev­i­dence,’ and let it sim­mer.”

It sim­mered for 10 years. Mean­while, ev­i­dence stacked up that all sorts of hor­mones have a di­rect im­pact on the skele­ton, even sero­tonin and oxy­tocin, neu­ro­trans­mit­ters al­most syn­ony­mous with mood and bond­ing – not bone. Over­whelm­ingly, it sug­gested that hor­mones do much more than the old text­books de­scribe.

But what re­ally opened minds to FSH, Zaidi said, was a ma­jor U.S. study fol­low­ing more than 2,000 mid­dle-aged women over sev­eral years that “clearly showed the max­i­mum rate of bone loss” oc­curs two to three years be­fore a woman has her last pe­riod.

“[That] shocked a lot of peo­ple,” Zaidi said, “be­cause at that time,

es­tro­gen is pretty nor­mal, and FSH is ris­ing. So how could a de­cline of es­tro­gen be solely re­spon­si­ble for the bone loss? It couldn’t be.”

With that news, Zaidi and his team de­cided to cre­ate an an­ti­body, which, like gum around a key blade, would block FSH from “un­lock­ing” its re­cep­tors. They tested the an­ti­body on fe­male mice who had their ovaries re­moved and were mak­ing no es­tro­gen and on male mice.

As they sus­pected, the FSH blocker slowed the loss of bone. But what they didn’t ex­pect was that the an­ti­body would also make the mice more fit and lean.

“The same ma­chine that mea­sures bone den­sity also gives you a fat read-out,” Zaidi said, “and a post-doc came to me and said, ‘With the an­ti­body, I see some ma­jor re­duc­tion in fat.’ I said, ‘Just ig­nore it, it’s prob­a­bly not an ef­fect [of the blocker].”

But the post-doc came back with the same ob­ser­va­tion. And the more Zaidi thought about it, the more plau­si­ble it seemed. Menopause dis­rupts me­tab­o­lism, adds fat around the tummy and over time, phys­i­cal ac­tiv­ity can ta­per off as en­ergy lev­els de­cline. But could high FSH be re­spon­si­ble for all of that, he won­dered, “I thought if we’re right, this could be re­ally big.”

Zaidi reached out to his friend, Clif­ford Rosen, a se­nior sci­en­tist at the Maine Med­i­cal Re­search In­sti­tute, “who knows more­about fat than I do,” and told him, “I’m get­ting this very funky set of ob­ser­va­tions.”

Rosen of­fered to test the FSH blocker in his lab and, six weeks later, he phoned back and said, “We got ex­actly the same re­sult you got.”

“For the next two years, we vir­tu­ally re­pro­duced each other’s data in the other’s lab,” Zaidi said.

What their work showed is that fat cells, like bone, also have FSH re­cep­tors. And high FSH re­sults in the for­ma­tion of white fat – which is made up of large fat-stor­ing cells that make up “the bulk of fat you see on some­body’s tummy.” But when FSH lev­els drop, “white fat cells go down, the tummy goes down,” Zaidi said. “We think a bunch of [white fat] gets con­verted into beige or brown fat, which burns off more eas­ily and pro­duces en­ergy.

“That’s why we see in sep­a­rate ex­per­i­ments an in­crease in en­ergy in th­ese mice that have the an­ti­body.”

In evo­lu­tion­ary terms, higher FSH lev­els in later life may have made sense once upon a time: “One of the fun­da­men­tal func­tions of the skele­ton is to pro­vide the cal­cium for min­er­al­iza­tion of the fe­tal skele­ton,” Zaidi said. “So af­ter pro­cre­ation ceases, you lose the skele­ton and you make more white fat and you lose mus­cle.”

White fat, Blake ex­plained, rep­re­sents a stor­age of ex­tra calo­ries, and it hear­kens back to a time in hu­man his­tory when calo­ries could be scarce. “So some ar­gue that weight gain in menopause serves the pur­pose of pro­vid­ing ex­tra calo­ries dur­ing a time of life when age makes you more nu­tri­tion­ally vul­ner­a­ble.”

But in the mod­ern world where food is plenty, and many peo­ple work to be fit and ac­tive well be­yond midlife, low­er­ing FSH could aid their ef­forts. As Zaidi said: “We’re very con­fi­dent in that if you can limit FSH, ge­net­i­cally or phar­ma­co­log­i­cally, you can get pro­tec­tive ef­fects on bone and re­duc­tion in body fat.”

While that con­cept may be ex­cit­ing, Blake, who was not in­volved in the re­search, cau­tioned that much re­mains to be un­der­stood. “Is it a magic bul­let? Prob­a­bly not for you and me.”

There is cur­rently noth­ing on the mar­ket that blocks FSH, she said, and added, “You have to be very care­ful about just block­ing th­ese im­por­tant things in the body that have been with us through evo­lu­tion. The ques­tion is what else are you block­ing?”

Es­tro­gen, Blake ex­plained, works on the brain and the bones, on skin, liver, in the gut, the uterus, in col­la­gen, and on it goes. “So you start to put this list to­gether and re­al­ize it will be years of ba­sic science to un­der­stand pre­cisely how FSH works on the body.”

It may be that block­ing cer­tain re­cep­tors would be bet­ter than block­ing the ac­tual hor­mone, Blake spec­u­lated. “But much re­mains to be un­der­stood about this. With any po­ten­tial so­lu­tion, you have to ask what are the con­se­quences.”

In the mean­time, she en­cour­ages menopausal women and oth­ers in mid-life to con­tinue to be phys­i­cally ac­tive, watch their di­ets and choose foods right for their health. Green tea, she pointed out, stim­u­lates the body’s heat pro­duc­tion and helps to ac­ti­vate the brown fat that burns more eas­ily than white.

In the ex­per­i­ments so far, block­ing FSH did not ap­pear to have any neg­a­tive side ef­fects in the mice, said Zaidi, who is now work­ing on a hu­man ver­sion of the an­ti­body. Once pro­duc­tion is scaled up, it will be for­mally tested in rats to check for tox­i­c­ity and “only if it passes those tests can [the FSH blocker] be tested in hu­mans,” said Zaidi, who ex­pects the process will take three years.

“The ma­jor con­cern is not that it’s go­ing to have side-ef­fects,” he said, “My ma­jor con­cern is that it’s mouse data that may not work in peo­ple.

“If it doesn’t, then we’ll say, we tried … Now if it does work in peo­ple, then we’re in good shape.”

Dr. Mone Zaidi

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