Chapter 12: Aging and Death

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Welcome to the deep dive.

Today we're jumping into something pretty universal, something we maybe push aside sometimes, aging and mortality.

That feeling, you know, when it suddenly hits you that life is finite, it can be awe -inspiring maybe a bit, I don't know, bitter.

Robert Sapolsky, whose work we're exploring today, he suggests this awareness often kicks in around puberty.

He even mentions that Woody Allen scene from Annie Hall.

Oh yeah, the universe is expanding kid.

Exactly, that feeling of despair.

Sapolsky sees it as this moment we get initiated into the big secret we know we're going to die and once you know that, well, it shapes so much, doesn't it?

Our fears, our ambitions, what we eat, how we exercise, even our myths of, you know, paradise.

It really does and what's fascinating and Sapolsky highlights this is how differently cultures grapple with aging.

Here in the West there's often a lot of anxiety.

He shares this really powerful story from his time in East Africa studying baboons.

He met this very old Maasai man, maybe 60, and the man was clearly frail, infected, sore, nearly blind from cataracts, and his neighbor just matter of

Just like that.

Wow, that's blunt.

Incredibly and Sapolsky's reaction was profound.

He thought, you know, I'll take your malaria and parasites.

Just let me be as unafraid as you are.

That really hits home the cultural difference.

It does because for many of us the fears are so tangible, aren't they?

Pain, dementia,

losing dignity, feeling like time's just slipping away right when we figure things out.

And that brings us right to the core of this chapter and our deep dive today.

The deep link between aging and stress.

The Bolski focuses on two main ideas.

Okay, what are they?

First, that aging itself makes us less able to cope with stress and second, that stress might actually speed up the aging process.

Right, less resilience as we age and stress making aging happen faster.

Those are big ideas and that's our mission today, isn't it?

To really unpack the evidence Sapolsky presents for these two.

Well, kind of unsettling concepts.

We'll walk through the science and maybe we'll get you thinking about your own life, longevity and how we handle everyday pressures.

So let's tackle that first question.

How well do older bodies handle stress?

You said Sapolsky's answer is pretty stark.

Yeah, basically not very well.

He frames aging in a way as this progressive loss of the ability to deal with stressors.

It's why older people might seem more fragile or vulnerable when things go wrong.

Okay, so it's not necessarily about how they are at rest, but how they react.

Exactly, that's the crucial distinction.

Young and old might look quite similar when everything's calm, but throw in a stressor, physical, mental illness, time, pressure, even just something new and that's when you see the declines in older individuals become really apparent.

Let's take some examples.

Thermoregulation.

Keeping body temperature stable.

Right, your internal thermostat.

So if you take a healthy older person and just mildly warm them up or cool them down, it takes them significantly longer to get back to their normal body temperature, that state of balance homeostasis, than a younger person.

So their system has to work harder just to get back to normal?

Precisely.

Now, think about the cardiovascular system.

Your heart and blood vessels.

Even in healthy older folks, without heart disease, their system shows a bigger decline under stress.

Things like

maximal heart rate, how fast your heart can beat, stroke volume, how much blood is pumped each beat,

muscle stiffness, how much blood the heart holds.

Technical terms, but the point is...

The bottom line.

The bottom line is these key measures drop more dramatically under stress in older people.

That's why, you know, even if an 80 -year -old seems fine sitting down, maybe running a marathon isn't advisable.

Their system just can't ramp up the same way.

Okay, so physical responses are slower, less robust.

What about the brain?

Same pattern there.

Brain function, cognition.

It's all less resilient.

For instance, after brain damage.

Surviving neurons usually sprout new connections to compensate.

Like rewiring.

Kind of, yeah.

Well, that happens in older brains too, but it's significantly slower for the same level of injury.

Or consider energy reserves in the brain.

At rest, young and old rat brains might have similar energy levels, like ATP or creatine.

The fuel for the cells.

Exactly.

But if you deprive those brains of oxygen and nutrients of major stress, the older brains burn through their energy stores much, much faster.

And cognition, like thinking.

Yeah.

IQ tests are a good example.

Give young and old people plenty of time.

Scores can be pretty similar, but add stress like a time limit.

Everyone's score drops a bit, that's normal, but the drop is much bigger for the older individuals.

So across the board, temperature, heart, brain repair, energy, even thinking under pressure, older systems show less resilience.

That's the picture Sapolsky paints, yes.

Produced resilience when challenged.

Is there a hormonal reason behind this?

Does the stress response system itself change with age?

Absolutely.

That's a huge part of it.

The hormonal stress response gets dysregulated.

There are two main problems, really.

Okay, what's the first?

Sometimes the response is actually inadequate where you'd expect it to be strong, like during exercise.

Older people might secrete more epinephrine and norepinephrine, those immediate adrenaline type hormones.

You'd think that would boost performance.

You would.

But as we just said, their cardiovascular system doesn't respond as vigorously.

Their maximal heart output still declines.

So, more hormone signal, but less physical response.

The effort doesn't translate.

Interesting.

And the second problem.

This one's arguably bigger.

Older organisms are just plain sluggish at shutting the stress response off.

So the all clear signal is delayed.

Exactly.

It takes much longer for the stress to decline after the stress is gone.

Sapolsky showed this clearly with rats.

Immobilize young and old rats, same stress, similar initial burst of glucocorticoids.

These are the longer acting stress hormones.

Right.

Cortisol in humans.

That's right.

But when the stress stopped,

the young rats' levels returned to normal at least twice as fast as the old rats.

And that delay has consequences.

It does.

Sapolsky found certain tumors grew faster in old stressed rats.

His hunch was it was due to these lingering glucocorticoids.

So they did a clever follow -up.

They took young rats, stressed them, and then gave them extra glucocorticoids after the stress, mimicking the old rats' slow shutoff.

And those young rats also showed faster tumor growth.

It really underlines the cost of that delayed all clear.

Those hormones hanging around are doing damage.

Okay.

Slow shutoff is a big issue.

What else?

Well, related to that, older organisms often have higher resting levels of stress even when nothing stressful is happening.

So their baseline is higher?

Yeah.

Higher resting epinephrine, norepinephrine, and glucocorticoids in old rats and humans.

Interestingly,

earlier human studies didn't always see this with glucocorticoids.

Because they often defined old as maybe 60s, early 70s.

But modern studies, looking at people in their late 70s and 80s, they find a significant jump in resting glucocorticoids.

And Sapolsky saw this in wild animals too.

Yes, in his wild baboon research.

Older baboons also had higher baseline glucocorticoids.

And that study is so valuable because it avoids all the usual human confounds,

diet, activity levels, medications, genetics.

These are, as he puts it, supremely healthy beasts, yet they still show this elevated baseline.

And what's the impact of that chronically higher level?

It likely contributes to things like age -related high blood pressure.

And it probably makes it harder for brain neurons to recover and sprout those new branches after injury that we talked about.

So let me recap.

The ideal stress response should be quiet at rest, fast and strong in an emergency, and then shut off immediately after.

That's the ideal, yes.

But in aged individuals, it tends to be the opposite.

Noisier at rest, maybe less effective during the crisis, and slow to turn off.

That sums it up pretty well.

It's like the system loses its precision and efficiency.

Which leads us perfectly into the second big question.

Can stress actually make you age faster?

It feels intuitive, but what's the science say?

Well, the idea has been around a long time.

These early wear and tear theories tried to capture it.

Like what?

There's Max Rubner, a German physiologist.

He had this idea of a lifetime metabolic rate, like each pound of tissue has a fixed amount of metabolism it can do.

So faster metabolism means you use up your allotment quicker.

Kind of.

Species with faster heartbeats, like rats, would burn through theirs faster than, say, elephants.

He even thought individuals who were overly nervous might squander their heartbeats and shorten their lifespan.

Have those ideas held up?

Not perfectly in their strictest forms, but they definitely paved the way.

Hans -Li, the stress pioneer, also talked about adaptational energies being depleted by lifelong stress, leading to faster aging or senescence.

Though adaptational energies was a bit vague.

Okay, so early ideas pointed in this direction.

How does Sapolsky connect it more concretely?

He brings it back to those glucocorticoids.

Remember all the problems linked to having too much glucocorticoid.

Fatigue, muscle thinning, diabetes risk, hypertension,

osteoporosis, weaker immune system.

Right.

And all of those things become more common as we age.

So the question becomes,

could glucocorticoid excess actually drive the aging process, at least in some cases?

And the answer is?

In some species, dramatically so.

Sapolsky highlights this idea of programmed death, using Pacific salmon as a prime example.

Ah, the salmon run.

Incredible journey, then.

Then they die, pretty much all of them, within weeks of spawning.

It's rapid, synchronized aging and death.

And glucocorticoids are the trigger.

They're the direct cause, the proximal mechanism.

After spawning, their hormonal system goes into overdrive, pumping out massive amounts of glucocorticoids.

But the shutoff mechanism fails completely.

They're flooded.

Is there proof?

Yes.

If you surgically remove a salmon's adrenal glands, the source of glucocorticoids right after spawning, they live longer.

And the truly bizarre thing.

This exact same mechanism, programmed death via massive glucocorticoid overload, has evolved independently in five different salmon species, and about a dozen species of marsupial mice in Australia.

Completely unrelated animals.

Completely unrelated.

Yet they arrived at the same fatal endpoint using the same hormonal pathway.

It's a striking evolutionary convergence, linking stress hormones directly to rapid aging and death.

Okay, salmon and marsupial mice are fascinating, but they're pretty extreme cases of rapid programmed death.

Does this apply to the slower, more gradual aging we see in mammals like us?

Sapolsky argues it does.

And in a pretty frightening way, it comes back to those elevated resting glucocorticoid levels we see in very old mammals.

And the faulty regulation.

Exactly.

The breakdown of that negative feedback loop.

Remember the toilet bowl analogy?

It's a float rising to shut off the water.

Right.

That's negative feedback.

Your hormonal system works similarly.

The brain senses glucocorticoid levels.

If they're high enough, it signals to stop making more.

It maintains a set point.

There's a clinical test for this, the dexamethasone suppression test.

Dexamethasone is a synthetic glucocorticoid.

You give it to someone.

And a healthy brain should sense it and stop making its own.

Precisely.

They're dexamethasone responsive.

But old rats, old primates, and older humans often become dexamethasone resistant.

They keep secreting their own hormones even with that strong signal.

The feedback loop is broken.

Why does it break down?

The evidence points strongly to degeneration in a key brain area.

The hippocampus.

Which is crucial for memory and learning.

And it's packed with glucocorticoid receptors, making it super sensitive to these hormones.

It acts like a major sensor in that feedback loop.

And the hippocampus degenerates with age.

It's one of the few areas that consistently shows significant neuron loss in normal aging.

Maybe 20 percent.

Not the whole brain, that's a myth.

But the hippocampus definitely takes a hit.

So damage the hippocampus.

And you damage the break on the glucocorticoid system.

You get the exact problems we see in aging.

Too much glucocorticoid secretion, trouble shutting off the stress response, dexamethasone resistance.

Okay, I see the connection.

But here's the crucial question.

What causes the hippocampus to degenerate in the first place?

And here, Sapolsky delivers the bombshell.

The neurons in the aging hippocampus likely die because of a lifetime of exposure to glucocorticoids themselves.

Wait, the hormones cause the damage that leads to more hormones?

That's the vicious cycle.

The research build over decades.

Early hints in the 60s, mapping receptors in the 70s by McEwen.

Then studies in the 80s, including Sapolsky's own, showing that stress levels of glucocorticoids, or just prolonged stress, speed up hippocampal aging and memory loss in rats.

So it's a degenerative cascade.

Glucocorticoids damage the hippocampus.

Which weakens the negative feedback break.

Leading to more glucocorticoid secretion.

Which causes more hippocampal damage.

And round and round it goes.

Truly insidious.

That is a chilling feedback loop.

How exactly do the glucocorticoids damage the neurons?

Do they just kill them out, right?

It seems they don't directly kill them, not usually.

Instead, they make the neurons more vulnerable to other things that can go wrong.

They endanger them.

Okay, vulnerable how?

It seems to tie back to energy.

Glucocorticoids mess with how hippocampal neurons handle energy.

Especially during a crisis.

Like a stroke or a seizure.

Exactly.

Those are energy crises for brain cells.

Glucocorticoids seem to block glucose, the main fuel from getting into hippocampal neurons efficiently.

It's similar to how they divert glucose to muscles during stress.

So during a stroke or seizure, when the neuron desperately needs energy,

glucocorticoids make it harder to get that fuel.

That seems to be the mechanism.

It makes the energy crisis worse, potentially pushing already struggling neurons over the edge.

Is there experimental evidence for this?

Yes.

In rat studies, if you give extra glucocorticoids after a seizure, you see worse hippocampal damage.

If you remove their adrenal glands so they can't make glucocorticoids, you see less damage.

Even neurons in a dish show this add glucocorticoids during an insult like low oxygen and more neurons die.

Wow.

So the body's own stress response can actually worsen brain damage in those situations.

It appears so.

It's been a long -standing controversy, actually giving glucocorticoids to people after stroke or head trauma to reduce swelling.

This research strongly suggests that might be counterproductive for the hippocampus.

So using non -steroidal alternatives might be better?

That's what many clinicians argue, yes.

And it's not just about giving external glucocorticoids, the body releases massive amounts internally after a neurological crisis.

Blocking that internal surge, say, by removing adrenals in rats or using drugs that temporarily block secretion also reduces hippocampal damage after stroke or seizure in animal models.

It seems like such a maladaptive response, though.

Why would the body do that?

Evolutionarily, it probably just wasn't selected against.

Until very recently in our history, surviving a major stroke or seizure was rare, so there wasn't strong pressure to evolve a different stress response for those specific, usually fatal situations.

Okay, the evidence in rats seems strong.

How much does this apply to human aging and brain diseases?

That's the million dollar question.

And it's much harder to study directly in humans.

We have to be cautious.

The full extent of this glucocorticoid neurotoxicity in human aging or in diseases like Alzheimer's isn't fully nailed down.

But there are hints.

There are hints.

We know stress and glucocorticoids damage primate hippocampi, which are very similar to ours.

People taking high -dose synthetic glucocorticoids for long periods for arthritis,

asthma, autoimmune diseases often report memory problems.

And older studies on people with Cushing's disease, who have naturally massive glucocorticoid levels, showed memory issues and some evidence of brain changes, though those studies were less precise.

So the potential is there.

The potential is definitely there.

And if this mechanism does operate significantly in humans, it represents a particularly profound threat, doesn't it?

Because damage to the hippocampus, to our memory, fundamentally changes who we are.

It's not just physical decline.

It's potentially losing our sense of self.

That's a deeply haunting aspect of aging.

Well, this has been quite the journey through Sapolsky's insights.

We've seen pretty clearly how aging seems to reduce our resilience to stress across the board.

And then this really powerful idea that chronic stress, especially through glucocorticoid excess, might actually accelerate parts of the aging process, particularly harming the hippocampus, that vital hub for memory.

Absolutely.

And maybe a final thought for you to ponder is that very vicious cycle we discussed, that degenerative cascade where the damage feeds itself.

Glucocorticoids harming the hippocampus, leading to poor regulation, leading to more glucocorticoids, leading to more damage.

It really highlights just how complex and intertwined the relationship between stress, our hormones, our brains, and the aging process truly is.

It's a sobering cycle, but understanding it is crucial.

It certainly is.

A lot to think about there.

From the entire Deep Dive team, thank you for joining us as we explored aging and stress through the lens of Robert Sapolsky's work.

We hope it gave you some valuable insights.

Thank you for listening.