Midlife Metabolism: Why You Gain Visceral Fat with Age and What to...
Nick Norwitz MD PhD@nicknorwitz
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Jul 27, 2025
~3 min read
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Midlife Metabolism: Why You Gain Visceral Fat with Age and What to Do About It (🔗 in 5/5)
1/5) A new 2025 paper was just published in Science that shines a light on why people gain visceral fat #VAT when they start to approach middle age.
Visceral fat sits around your internal organs, and beyond presenting as an aesthetically upsetting beer gut, it spits off inflammatory signaling molecules, contributes to poor cardiovascular health, cognitive decline, and can even cause muscle loss, laying the groundwork for what’s known as sarcopenic obesity (lots of fat with little muscle).
Like invasive weeds choking out a garden, visceral fat disrupts the delicate balance of the metabolic ecosystem.
#visceralfat #fatloss #longevity #healthyaging #inflammation #staycurious
1/5) A new 2025 paper was just published in Science that shines a light on why people gain visceral fat #VAT when they start to approach middle age.
Visceral fat sits around your internal organs, and beyond presenting as an aesthetically upsetting beer gut, it spits off inflammatory signaling molecules, contributes to poor cardiovascular health, cognitive decline, and can even cause muscle loss, laying the groundwork for what’s known as sarcopenic obesity (lots of fat with little muscle).
Like invasive weeds choking out a garden, visceral fat disrupts the delicate balance of the metabolic ecosystem.
#visceralfat #fatloss #longevity #healthyaging #inflammation #staycurious
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2/5) Now, just to caveat up front: most of the experiments were necessarily done in mice, since the techniques needed to unravel this mushy metabolic mystery required genetic manipulation. Still, as you’ll see, the findings appear highly relevant to humans too.
Anyway, what they found first is that male mice, upon approaching middle age, started to pack on fat while also losing muscle. Total body fat naturally increased by >6-fold, while lean mass decreased by 23%. Most of the body fat gain was in visceral fat. Along with these changes, basal metabolic rate dropped, indicating a slower metabolism, and the mice became insulin resistant.
What The GFP is going on?!
Anyway, what they found first is that male mice, upon approaching middle age, started to pack on fat while also losing muscle. Total body fat naturally increased by >6-fold, while lean mass decreased by 23%. Most of the body fat gain was in visceral fat. Along with these changes, basal metabolic rate dropped, indicating a slower metabolism, and the mice became insulin resistant.
What The GFP is going on?!
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3/5) Well, now I need to explain two ways in which fat grows.
👉Hypertrophy: Mature, existing fat cells can grow larger.
👉Adipogenesis: New fat cells grow from precursor stem cells called Adipose Progenitor Cells (APCs).
Now here’s the funny thing about APCs as stem cells: most stem cells lose their capacity to multiply and renew as we age. But for APCs, it’s the opposite!
In young animals and humans, APCs are “quiescent” – calm, dead to the world. But then something happens around middle age and they develop the capacity to blossom into visceral fat like.
Think of them like sleeper agents in a spy movie — lying low for decades until suddenly activated with a secret code to carry out a covert mission… of fat expansion.
I know, Nature has a sick sense of humor.
How to interpret this graph: Green stains mature fat cells. Red stains all fat cells. The right column includes the overlap or “merge.” If, in this column, there’s a lot of visible red it suggests large spike in adipogenesis.
👉👉TLDR: With age, there is a large spike in the development of new visceral fat cells
👉Hypertrophy: Mature, existing fat cells can grow larger.
👉Adipogenesis: New fat cells grow from precursor stem cells called Adipose Progenitor Cells (APCs).
Now here’s the funny thing about APCs as stem cells: most stem cells lose their capacity to multiply and renew as we age. But for APCs, it’s the opposite!
In young animals and humans, APCs are “quiescent” – calm, dead to the world. But then something happens around middle age and they develop the capacity to blossom into visceral fat like.
Think of them like sleeper agents in a spy movie — lying low for decades until suddenly activated with a secret code to carry out a covert mission… of fat expansion.
I know, Nature has a sick sense of humor.
How to interpret this graph: Green stains mature fat cells. Red stains all fat cells. The right column includes the overlap or “merge.” If, in this column, there’s a lot of visible red it suggests large spike in adipogenesis.
👉👉TLDR: With age, there is a large spike in the development of new visceral fat cells
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4/5) Ultimately, the researchers revealed that the mechanism was related to the LIFR-STAT3 pathway. Importantly…
(1) This LIFR-STAT3 pathway is also active in the fat of middle-aged humans. You can see on the left a graph of these LIFR fat cells and how they increase, rather linearly, with age. And, on the right, you can see a stain for these cells in a 29-year-old man versus a 64-year-old man. Clearly, there are more of these fat cells, born of adipogenesis, in the older man.
(2) Silencing the LIFR-STAT3 pathway was effective at inhibiting adipogenesis and visceral fat gain. This is great news and where our story takes an optimistic turn, because there are ways to inhibit this pathway and – potentially – slow or halt adipogenesis closer to youthful levels.
(1) This LIFR-STAT3 pathway is also active in the fat of middle-aged humans. You can see on the left a graph of these LIFR fat cells and how they increase, rather linearly, with age. And, on the right, you can see a stain for these cells in a 29-year-old man versus a 64-year-old man. Clearly, there are more of these fat cells, born of adipogenesis, in the older man.
(2) Silencing the LIFR-STAT3 pathway was effective at inhibiting adipogenesis and visceral fat gain. This is great news and where our story takes an optimistic turn, because there are ways to inhibit this pathway and – potentially – slow or halt adipogenesis closer to youthful levels.
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5/5) Now, if you want more about aging, visceral fat, and what natural compounds might act on this newly discovered LIFR-STAT3 pathway to block adipogenesis, read today’s StayCurious Metabolism Newsletter. I aim to make it worth your time! staycuriousmetabolism.substack.com/p/midlife-meta…
