Immunometabolism & Aging - The Dixit Lab at Yale School of Medicine

Transcript

• 00:05It has become very clear
• 00:07that aging is not just
• 00:08fait accompli. Aging is a
• 00:10malleable process.
• 00:12And it turns out that
• 00:13almost every intervention
• 00:16that extends lifespan and reduces
• 00:19disease burden in animals
• 00:21is a metabolic intervention.
• 00:23But there are also
• 00:24molecular
• 00:26pathways
• 00:27and sensors
• 00:28in the body that sense
• 00:30the energy that is available
• 00:31to cells.
• 00:33And if those are targeted,
• 00:34that extends lifespan.
• 00:36And when that happens, one
• 00:38of the things that's really
• 00:39exciting is that the immune
• 00:40system,
• 00:41which basically resides also in
• 00:43every organ,
• 00:45is rewired
• 00:47to have greater ability to
• 00:49repair the damage that occurs
• 00:51with age. So immuno metabolism
• 00:53or this interaction between these
• 00:55two systems, we think, has
• 00:56a lot of potential in
• 00:57terms of understanding the basic
• 00:59biology of the aging process.
• 01:04So we are interested in
• 01:05these two phenomenas where
• 01:08the thymus, this organ that
• 01:10produces protective t cells in
• 01:11the body that controls infections,
• 01:13but we also know it
• 01:14controls cancers.
• 01:16What happens is that this
• 01:17organ ages so fast.
• 01:19By the age of forty
• 01:20five, in a healthy human
• 01:22being,
• 01:23almost eighty five percent of
• 01:25the human thymus
• 01:26is made up of fat.
• 01:28So it's an organ that's
• 01:29supposed to produce immune cells,
• 01:30but it has now fat
• 01:31cells in it.
• 01:32And the other end of
• 01:34the spectrum is the fat
• 01:35itself. The adipose tissue expands
• 01:38with age. Even if you
• 01:39maintain your normal body mass
• 01:41index, the fat that increases
• 01:43is called the visceral fat,
• 01:44the fat that lines our
• 01:45organs, internal organs.
• 01:48And what happens, very unique
• 01:50in this situation with aging,
• 01:51is that
• 01:52as that fat is expanding,
• 01:54the things that expand inside
• 01:56the fat are the immune
• 01:57cells.
• 01:58So on the other hand,
• 01:59you have thymus where it's
• 02:01supposed to produce the immune
• 02:02cells. It has now fat
• 02:03cells expanding in it. And
• 02:05then you have an adipose
• 02:06tissue whose whole purpose is
• 02:07to control metabolism,
• 02:09has now this excessive immune
• 02:10cell infiltration.
• 02:12And what's now becoming clearer
• 02:13is that
• 02:15both these processes
• 02:16actually converge to produce inflammation,
• 02:19which is now one of
• 02:20the central features that controls
• 02:22degenerative changes that happen with
• 02:25age.
• 02:29What we're trying to do
• 02:31is to
• 02:33really understand
• 02:34what are the mechanisms that
• 02:35are now dormant in humans
• 02:37that are living in the
• 02:38modern world. Because when we
• 02:40hit these dormant pathways,
• 02:42it actually extends lifespan in
• 02:43animals.
• 02:45Calorie restriction is a very
• 02:46good example of it. Okay?
• 02:48If you reduce the amount
• 02:49of calories that you're consuming,
• 02:51now there are adaptive mechanisms
• 02:53that we never actually have
• 02:54to utilize in our modern
• 02:56life that are now upregulated.
• 02:58Okay? And we want to
• 02:59harness that.
• 03:01So we're very much interested
• 03:02in nature. So there is
• 03:03this species that lives in
• 03:05the desert in Middle East.
• 03:07It's very unique in the
• 03:08sense that it lives close
• 03:09to six times longer
• 03:11in the desert.
• 03:13And this species of golden
• 03:14spiny mouse is extremely resilient
• 03:17to age related decline.
• 03:20And we're trying to understand
• 03:21what is
• 03:22present in this species that
• 03:24is now dormant in us.
• 03:29So the hope obviously is
• 03:31that these mechanisms that we're
• 03:33trying to understand that become
• 03:34dysfunctional with age
• 03:36and identify which ones are
• 03:38actually the drivers of that
• 03:39process of aging
• 03:41versus the ones that are
• 03:42just passengers.
• 03:44And one of the things
• 03:45that we have discovered along
• 03:46with several of our colleagues,
• 03:48across the world
• 03:49is a sensor
• 03:51in the immune system
• 03:53which senses damage. The sensor
• 03:55is called as the NLRP
• 03:56three inflammasome.
• 03:57It's a long, long, complicated
• 03:59name.
• 04:00But it is now becoming
• 04:02more and more clear
• 04:04that,
• 04:04as people are doing, you
• 04:06know, the omic studies in
• 04:07humans and in animals across,
• 04:09time span,
• 04:11that this mechanism, NLRP three,
• 04:13gets upregulated
• 04:14with age, something that we
• 04:15had been studying for close
• 04:17to fifteen years now.
• 04:18And if you lower it,
• 04:21you can not only extend
• 04:22lifespan in the animals, you
• 04:23actually reduce
• 04:24the onset of diseases.
• 04:27And good news is it's
• 04:28actually imminently druggable.
• 04:31So the hope obviously
• 04:32is that these mechanisms that
• 04:34we and others are discovering
• 04:36are eventually targetable. And if
• 04:37they are targetable, then whether
• 04:39that actually improves the health
• 04:40of older adults.
• 04:42And, obviously, you know, this
• 04:43has huge implications
• 04:45for for all of us
• 04:46because aging affects everyone.