Mitochondria & Aging | Modern Healthspan Clips

Summary

This video discusses the critical role of mitochondria in cellular health and aging. Mitochondria, often referred to as the 'powerhouses' of the cell, are essential for energy production and participate in numerous cellular processes. As we age, mitochondrial dysfunction is linked to neurodegeneration, making early detection crucial. The video delves into the complexity of mitochondria, their genetic uniqueness, and their heterogeneity across different tissues. It also explores the concept of mitophagy, a process that removes damaged mitochondria, and the importance of maintaining mitochondrial health through interventions like exercise and supplementation with magnesium. The discussion highlights the potential of mitochondrial microproteins in treating age-related diseases and the ongoing research in this field.

Takeaways

• 🧬 Mitochondria are essential cellular organelles with numerous functions, including energy production and participation in various cellular processes.
• 📉 With aging, there is a loss of mitochondria and a decline in their function, which is an early indicator of neurodegeneration.
• 🔬 Mitochondria are heterogeneous, with different sizes, functions, and genetic backgrounds, making their study complex.
• 🧬 Mitochondria contain their own genome, separate from the nuclear genome, which is simpler and contains genes for energy production and other functions.
• 📊 Aging affects mitochondrial function, leading to changes in energy production and structure, which can be measured through various clinical methods.
• 🧐 Mitophagy is a process that removes damaged mitochondria and is crucial for maintaining cellular health and preventing neurodegeneration.
• 💊 The peptide humanin, encoded in mitochondrial DNA, has been shown to have beneficial effects on aging and cognitive decline.
• 🔍 Scientists are discovering many small open reading frames in mitochondrial DNA that can encode microproteins with potential roles in aging and disease.
• 🏋️‍♂️ Exercise can stimulate the production of beneficial mitochondrial microproteins, such as Moi, which has potential roles in weight loss and muscle health.
• 💡 Magnesium is crucial for cellular function and supports optimal mitochondrial function, potentially reducing oxidative stress and cellular aging.
• 🧪 Mitochondria from different tissues have distinct functions and produce different peptides, indicating the importance of context-specific mitochondrial health.

Q & A

What are mitochondria and why are they important for our health?

Mitochondria are small organelles found in the cytoplasm of cells, with multitudes per cell. They have many functions, including energy production in the cell, which is one of their most important roles. They also participate in numerous other processes and interact with the cellular environment and nuclear processes. Mitochondria are crucial for health as they play significant roles in aging and are targeted for their dysfunction as an early indicator of neurodegeneration.

How do mitochondria change as we age?

With aging, there is a loss of mitochondria and a loss of function in them. Energy production can decrease or become dysfunctional. The structure of mitochondria changes, and their organization within the cell is also altered. These changes are observed early in neurodegeneration and other diseases.

How can we measure mitochondrial function?

Mitochondrial function can be measured directly with energy production measurements using sophisticated equipment. Additionally, electron microscopy can be used to observe the structure and organization of mitochondria, including how many there are and their size variations.

What is mitophagy and how does it help with mitochondrial health?

Mitophagy is a targeted process of autophagy that gets rid of bad or dysfunctional mitochondria. It helps maintain overall mitochondrial function by ensuring that only healthy mitochondria remain in the cell, which is crucial in preventing the accumulation of dysfunctional mitochondria that can cause problems in the cell.

How do mitochondria regenerate themselves?

Mitochondria can be disposed of and new ones generated through a process that involves both fission, where mitochondria divide, and fusion, where they merge to form a network. This dynamic process helps maintain a healthy population of mitochondria within cells.

What is the significance of mitochondrial DNA and how does it differ from nuclear DNA?

Mitochondrial DNA is a small, circular genome with only a few genes that code for mitochondrial energy function. It differs from nuclear DNA, which has a large genome with thousands of genes and a complex structure. Mitochondrial DNA is also unique because it is inherited maternally, unlike nuclear DNA.

What is the role of microproteins encoded by mitochondrial DNA?

Microproteins encoded by mitochondrial DNA, such as humanin, have been found to have various beneficial effects on health, including protecting the brain from cognitive decline, delaying aging processes, and preventing diseases like Alzheimer's and diabetes. They are considered important in aging due to their role in repairing and correcting biological processes.

How does the mitochondrial peptide humanin impact health and aging?

Humanin is a novel small peptide encoded in mitochondrial DNA that, when secreted and circulated in the body, has been shown to protect against cognitive decline, fibrosis, and atherosclerosis. It is considered a quintessential mitochondrial peptide with significant roles in aging and disease prevention.

What is the potential role of magnesium in supporting mitochondrial function?

Magnesium is a critical mineral for cellular function, particularly as it is bound to ATP, the cellular energy currency. Magnesium deficiency may contribute to oxidative stress, accelerated cellular aging, and mitochondrial dysfunction. Supplementing with magnesium, such as through Magnesium Breakthrough, can support optimal mitochondrial function.

Do mitochondria from different tissues function differently?

Yes, mitochondria from different tissues like brain, liver, and muscle are very different. They have distinct energetic profiles, proteomic distributions, and functions, which can be influenced by disease states and interventions.

How does the process of mitophagy decline with age and impact mitochondrial health?

As we age, the efficiency of mitophagy declines, leading to an accumulation of dysfunctional mitochondria that cannot be removed as effectively. This results in increased oxidative stress and reduced energy generation, contributing to cellular aging and the development of age-related diseases.

Outlines

00:00

🧬 Mitochondria's Role in Aging and Health

The video script begins by discussing mitochondria, the cell's energy-producing organelles, and their importance to health. It explains that mitochondria are not only vital for energy production but also participate in numerous other cellular processes. As people age, there is a decline in both the number and function of mitochondria, which is linked to neurodegenerative diseases like Alzheimer's. The speaker expresses interest in targeting mitochondrial dysfunction as an early sign of such diseases. Various methods to measure mitochondrial function are discussed, including energy production measurements and electron microscopy to observe mitochondrial structure. The script also touches on the genetic aspects of mitochondria, which are inherited maternally and have a simpler genome compared to the nuclear genome.

05:00

🧬 Mitochondrial Changes and Mitophagy

This paragraph delves into the complexities of mitochondrial aging and the concept of mitophagy. Mitochondria are heterogeneous, with different sizes and functions, and their genetic material is matrilineal. The script explains how mitochondria can regenerate and be disposed of, but as they age, they can't generate new ones that are younger. The process of mitophagy, which is the targeted destruction of damaged mitochondria, is highlighted as crucial for maintaining cellular health. The importance of effective mitophagy in preventing the accumulation of dysfunctional mitochondria and its role in diseases like neurodegeneration is emphasized. The unique features of mitochondria, such as their own chromosome and the discovery of additional genes within mitochondrial DNA, are also discussed.

10:02

🧬 Mitochondrial Peptides and Their Impact on Aging

The script introduces the concept of mitochondrial peptides, small proteins encoded within the mitochondrial DNA that have significant biological roles. One such peptide, humanin, is highlighted for its protective effects against cognitive decline and other aging-related issues. The discovery of numerous small open reading frames within mitochondrial DNA, which could potentially translate into hundreds of microproteins, is discussed. The importance of these microproteins in aging is underscored, as their production decreases with age, potentially leading to diseases like diabetes and Alzheimer's. The script also mentions other mitochondrial peptides, such as SCHLAP2 and MOI, which show promise in combating aging and related conditions.

15:04

🧬 Tissue-Specific Mitochondrial Function and Peptides

This section of the script emphasizes the variability of mitochondria across different tissues. It explains that mitochondria from brain, liver, and muscle are distinct in their appearance, proteomic profiles, and energetic functions. The development of a technique akin to RNA sequencing, but for analyzing mitochondrial peptides, reveals that the expression of these peptides varies significantly from tissue to tissue and is sensitive to disease states and interventions. The script suggests that understanding these tissue-specific mitochondrial peptides could be key to addressing various diseases and conditions associated with aging.

20:04

🧬 Mitochondrial Dynamics and Aging

The script discusses the dynamic nature of mitochondria, which are constantly generated and replaced to maintain cellular homeostasis. It explains the processes of mitochondrial biogenesis and mitophagy, which are crucial for clearing damaged mitochondria. The importance of mitochondrial dynamics, such as the fragmentation and networking of mitochondria, is highlighted in relation to metabolic efficiency and the ability to be cleared by mitophagy. As aging occurs, the script notes a decline in these processes, leading to the accumulation of dysfunctional mitochondria, increased oxidative stress, and a decrease in energy generation, which can contribute to cellular damage and disease.

25:05

🧬 Encouraging Mitophagy and Mitochondrial Health

The final paragraph explores ways to stimulate mitophagy to combat the decline in mitochondrial function associated with aging. It mentions genetic pathways that modulate mitophagy and the role of nutrient sensing in this process. The script also discusses the potential of pharmacological interventions, such as the use of ursolic acid, to promote mitophagy in tissues like the brain and muscle. The importance of maintaining mitochondrial homeostasis for overall health is reiterated, along with the potential benefits of supplements like magnesium for supporting optimal mitochondrial function.

Keywords

💡mitochondria

Mitochondria are the powerhouses of the cell, responsible for generating energy in the form of ATP. They are crucial for various cellular functions and are highlighted in the video as playing a significant role in aging and neurodegenerative diseases. The script discusses mitochondrial dysfunction as an early indicator of neurodegeneration, emphasizing their importance in health and aging.

💡aging

Aging is a natural process that involves the gradual decline of various bodily functions. The video script discusses how mitochondria change and dysfunction with age, leading to a decrease in energy production and contributing to diseases like Alzheimer's. Aging is a central theme, with mitochondria playing a key role in the aging process and related health issues.

💡mitochondrial dysfunction

Mitochondrial dysfunction refers to the impaired ability of mitochondria to perform their normal functions, such as energy production. The script mentions that with aging, there is a loss of mitochondria and a decline in their function, which can lead to neurodegeneration. This concept is vital for understanding the impact of mitochondria on health as we age.

💡mitophagy

Mitophagy is a cellular process that involves the degradation and recycling of damaged or dysfunctional mitochondria. The video script explains that mitophagy is important for maintaining healthy mitochondria and preventing the accumulation of bad mitochondria, which can cause problems in the cell. It is a targeted form of autophagy that is crucial for cellular health and combating aging.

💡neurodegeneration

Neurodegeneration refers to the loss of nerve cells, which can lead to cognitive decline and diseases like Alzheimer's. The script discusses how changes in mitochondrial function are among the earliest events in neurodegenerative processes, making the study of mitochondria critical for understanding and potentially treating such diseases.

💡microproteins

Microproteins, also known as micropeptides, are small proteins encoded by both the mitochondrial and nuclear genomes. The video script describes how these microproteins, such as humanin and schlep2, have various beneficial effects on health, including protection against cognitive decline and tissue damage, and are a growing area of scientific research.

💡humanin

Humanin is a specific microprotein encoded by mitochondrial DNA. The script highlights its role in protecting the brain from cognitive decline and delaying the onset of atherosclerosis. Humanin is an example of a mitochondrial-derived microprotein that has significant health benefits, particularly in the context of aging.

💡Moi

Moi is another mitochondrial microprotein discussed in the script, which has exercise-mimetic properties and can lead to weight loss and a reduction in fatty liver. It is an example of how mitochondrial microproteins can have direct effects on health and potentially be used in treating conditions related to aging.

💡mitochondrial DNA

Mitochondrial DNA (mtDNA) is the genetic material found within mitochondria, separate from the DNA in the cell nucleus. The script explains that mtDNA contains genes that code for proteins involved in energy production and that it also harbors many small open reading frames that can encode microproteins, which are important for various biological processes.

💡magnesium

Magnesium is a critical mineral for cellular function, particularly as it is bound to ATP, the primary energy currency of the cell. The script mentions magnesium deficiency as a potential contributor to oxidative stress, accelerated cellular aging, and mitochondrial dysfunction, emphasizing the importance of magnesium for maintaining optimal mitochondrial function.

Highlights

Mitochondria are essential for health, with functions beyond just energy production.

Mitochondrial dysfunction is an early indicator of neurodegeneration.

Mitochondria are heterogeneous, with different sizes and functions even within the same cell.

Mitochondrial genetics are matrilineal, with a simple genome distinct from the nuclear genome.

Aging is associated with a loss of mitochondria and a decline in their function.

Mitochondrial function can be measured directly with energy production measurements and electron microscopy.

Mitochondria regenerate themselves through processes of fusion and fission.

Mitophagy is a process that rids the cell of dysfunctional mitochondria, which is crucial for cellular health.

Mitochondrial DNA is more prone to damage, and its function declines more rapidly than nuclear function.

Mitochondria contain their own chromosome and can produce proteins within the mitochondria.

Humanin is a peptide encoded in mitochondrial DNA with beneficial effects on aging and cognitive decline.

Mitochondrial DNA contains many small open reading frames that can be translated into microproteins.

Microproteins from the mitochondria are believed to play a significant role in aging.

Schlep2 is a microprotein showing promise in translating into treatments for human diseases.

Moi is a microprotein with exercise-mimetic properties that could treat conditions like obesity and frailty.

Magnesium is crucial for cellular function, particularly in supporting mitochondrial function.

Mitochondria from different tissues have different functions and produce different peptides.

Mitochondrial DNA damage accumulates over a lifespan, but less functional mitochondria are eliminated through mitophagy.

Mitochondrial function and dynamics are essential for maintaining cellular homeostasis and adapting to metabolic needs.

As we age, the balance of mitochondrial function declines, leading to the accumulation of dysfunctional mitochondria.

Mitophagy can be encouraged through genetic pathways and pharmacological interventions, such as with ursolic acid.

Transcripts

[Music]

so what I'd like to talk about is

mitochondria and particularly how they

impact us as we get older but kind of

starting at the beginning kind of very

briefly what are mitochondria and why

are they so important to our

health yeah mitochondria are our little

organel we have in the cell multitudes

per cell of these small organ Els and

they have many

functions for for a long time people

thought they were just making energy in

the cell and that's one of their most

important functions but they also are

participate in multitudes of other

processes in the cell interact with the

environment in the cell with the nuclear

processes so the mitochondria are not

part of what we call the nucleus of the

cell they are around the nucleus they're

in a cytoplasm

of the cell but they play enormous

amounts of of uh important uh roles in

processes also in aging and so with

aging we know that there is a loss of

mitochondria there's also a loss of

function in the

mitochondria and uh we have begun to

Target mitochondrial dysfunction as a

very early indicator of neurod

degeneration so that is one of the

things that really attracts my interest

is that it seems to be one of the

earliest things that happen in the cell

is some changes with mitochondrial

function that then leads are the early

steps probably in Alzheimer's and other

neur

degenerations so it's very important to

understand these

changes at the earliest possible

stage so how do you how do you tell that

the mighty is is there any kind of

clinical way of telling your

mitochondria are not functioning

correctly yeah there are there are a

number of different ways and and

mitochondria by the way are very

heterogeneous we have different kinds of

mitochondria different sizes of

mitochondria different functions of

mitoch condia even within the same cell

so it makes it quite

complicated and then they are the

genetics rely on the the female rather

than the male as is well known and so

the whole organization in genetics and

and of mitochondria is is very

intriguing and while in the nucleus we

have a large genome with 20,000 genes

and very complex structure and

organization The genome that is found

inside the mitochondria is a very simple

small plasm or circular DNA with only

few genes that code for mitochondrial

energy function and and other proteins

other functions that are being brought

into the mitochondria are coded for by

the nuclear DNA so we have two different

genomes within one cell it can be the

mitochondrial genome and the nuclear

genome so how do how do mitochondria

change as they get old as we get old so

so we talk about the dysfunction in what

way are they

dysfunctioning yes so I you also

mentioned how do the how do we measure

mitochondria so

we can measure mondro function directly

with energy Pro measurements and in in

in in sophisticated equipment and we can

also look at the mitochondria with

electron microscopy and look at the

structure of the mitochondria

organization of mitochondria how many

mitochondria there are and other such

things so what's been observed is that

there are a number of things that go

wrong with mitochondria with aging

energy production can change usually go

down but can also be activated so it

gets

dysfunctional it gets out of wacko with

age in the mitochondri energy production

and then there are other processes the

mitochondria we can also observe the

structure of the mitochondria

changes the uh Fusion fish we call it

between how mitochondria organized

themselves is also changed so there are

a number of processes that change with

aging and also early on reur De

generation for example and other

diseases yeah I wanted to talk about the

disease but but one thought you know so

mitochondria they they generate

regenerate themselves right uh they

separate fusion and fish yeah and

fishion uh I mean if they're generating

new ones why are the new ones kind of

older can't they generate new ones which

are

younger yeah yeah it's a it's a it's an

interesting question yeah they they

could in a way but they really can't so

it depends on on a number of things also

the genetic background mitochondria and

and and many processes but they they you

have a we have a heterogeneous

population of mitochondria so they can

be mitochondria at different should we

say stages and ages within one

cell and and and makes it makes it it

complicated but mitochondria can also be

disposed of and new mitochondria

generated all the

time so I was gonna ask about that so so

mitophagy and the getting rid of the

existing mitochondria which seems to be

a way of helping with their health like

how does mitophagy help with the overall

function of

so

mitochondria get bad with aging and

neuro

degeneration neuro degeneration as we

just talked about in in different ways

and the process of replacing these

mitochondria getting rid of the bad ones

is the mitophagy process so we have a a

general process called autophagy in the

cells getting rid of cells more General

ways and then we have a targeted one

that gets rid of the bad mitochondria

and you can

actually tell that mitochondria are bad

if you will or dysfunctional in in for

example electron microscopy where the

structure looks um abnormal and it just

simply uh so they need to be disposed of

if we don't get rid of those bad

mitochondria they accumulate they they M

they they fill up and take and and

simply cause various problems in the

cell the bad mitochondria so we we

really need to have an effective process

of replacing the bad mitochondria and

that is done

by a special organization involving

lomes and and acidic milu in the cell

that then degenerates the mitochondria

that not

functional let me start with the

mitochondria so our body is made of

cells all cells except perhaps red blood

cells contain

mitochondria mitochondria have multiple

roles they are the energy source of the

cells uh they also have uh function as

immune Regulators as metabolic

Regulators as inducers of programmed

cell death and mondal dysfunction is

involved in many different diseases but

particularly in diseases of aging and

everything we said about age in general

applies to the mitochondria and Spades

mitochondria are much more prone to uh

DNA damage they uh their function

declines much more rapidly than nuclear

function and they accumulate neurom

mutations and uh uh see damage as we age

the one thing that makes the

mitochondria unique is it contains its

own

chromosome this chromosome is much

smaller than the nuclear chromosomes

it's only 16,000 base Bears which isn't

much and it contains 13 large protein

coding genes that are part of the

so-call respiratory chain that allows

the mondria to uh turn oxygen into

ATP and also has its own ribosome system

that allows it to produce proteins

Within theond Anda that was the thinking

up till 20 years ago when we and a

couple of other groups stumbled on an

observation that there is a small Gene

within a gene in the mitochondrial DNA

that uh a scientist who has already

passed away from Tokyo Japan named

nishimoto he named that prodin humanin

my lab cloned it at the same time that

he cloned humanin was the first to

recognize its importance and publish it

um we became friends in the early 2000s

and appropri fortunately he died from

cancer uh a little over 10 years ago

um humanin turned out to be this novel

small peptide encoded in mondal DNA we

believe it get uh the MRNA for human in

goes from the mitochondria to the Cy

plasm where it gets translated into this

little peptide 24 amino acid peptide

gets secreted out of the

cell and then circulates around the body

and has really tremendous beneficial

effects from protecting the brain from

cognitive decline from protecting aging

tissues from fibrosis and other damage

uh from delaying or preventing

atherosclerosis and and there are now

probably over 500 Publications from over

30 Laboratories around the world

demonstrated the various beneficial

effects of humanin in animal models

mainly mice and rats in in uh primarily

the context of

aging and so humanin is sort of the

quintessential mitochondrial peptide so

about 17 years ago 15 years ago uh in

one of our lab

meetings we started asking if there is

one small open reading frame hiding

inside a larger Gene why shouldn't there

be more of them and we started studying

the mitochondrial DNA looking for

additional open reading frames and by

now we realized that there are many

hundreds of them probably six or 7

hundred small open reading frames

Each of which can be conceptually

translated into a small peptide uh by

the way these days we like to call them

microproteins rather than micropeptides

that's the latest Trend and many many

hundreds of microproteins can

theoretically be made by the

mitochondrial

DNA we have now uh believe that we

identify dozens of these in the

mitochondria and the big change that

that happened in the field is that

people have started recognizing that

their microproteins these small open

reading frames that get translated

translated into peptides they exist also

in the nuclear

genome and there are actually hundreds

of thousands if not millions of small

open reading frames that can encode

microproteins in the nuclear genomes and

there are multiple groups working on

these in fact there was this really

interesting family of molecules known as

long n coding rnas that was discovered

about 15 to 20 years ago and by their

name it implies that they don't code for

any

protein now people are recognizing that

many of these long L coding rnas

actually do code for

microprotein so the science of

microproteins is

expanding we like to believe that we

started it and that we really are moving

the needle in the mitochondrial sphere

but many outstanding scientists are now

working on uh nuclearly encoded m u uh

microproteins that have important

biological roles I happen to believe

that these microproteins from the

mitochondria from the mitochondrial DNA

that we work on are particularly

important in aging precisely because

during the aging process there is so

much

damage to mitochondria and mitochondrial

DNA that the production of these

mitochondrial microproteins goes down

leading to uh poor performance of

certain things certain tissues certain

biological processes and resulting in

diseases like diabetes and Alzheimer's

disease and other diseases like fibrosis

which mitochondrial microproteins can uh

repair correct and

reverse so uh when we recognize that

there could be more mitochondrial

microproteins we started out initially

by just saying okay here's

humanin right next to it there's another

open reading frame let's see what that

one does and we named a bunch of them

small human like peptides or

schleps one of them is called schlep 2

and it's a very exciting microprotein

that we're working on been published now

in about 10 or 15 papers and to me it's

one of the most promising candidates

that can be translated into human

disease and whether that disease would

be Parkinson or some other condition

we're still unraveling but about a

decade ago and we published this in

2015 we noted that there was a small

open reading frame a little bit further

away from humanin which we called

Moi and Moi turned out to be a

fascinating

microprotein and it has uh exercise

mimetic and exercise enhancing

biological activity that result in

weight loss in my our obese or for high

fat diet um reduction in steatosis

or apotosis is fatty liver one of my

colleagues is not showing that it also

decreased something called myosteatosis

which is a really underappreciated

severe process of Aging where there's

fat accumulation in muscle and Mai uh

amarate that and reverses that so Mai

which is also regulated by exercise if

you exercise you secrete matsi uh is an

exciting peptide with potential roles in

a number of conditions from Frailty to

obesity to fatty liver and we licensed

this to the company uh Cobar that near

barcel I and myself founded a little

over a decade ago and it has completed

phase one studies and is now planning uh

phase two studies with Mai as well as um

identifying several other potential

important microproteins from the

mitochondria which uh they will

hopefully develop for additional

diseases of Aging such as uh idiopathic

pulmonary fibrosis and related condition

do you know magnesium is a critical

mineral for cellular function perhaps

the most important role is being bound

to ATP the currency of cellular energy

as magnesium ATP complex which is the

recognized form of the co-actor required

for proper function by hundreds of

enzymes research suggests that magnesium

deficiency can contribute to increased

oxidative stress accelerated cellular

aging and mitochondrial

dysfunction to make sure that we are not

deficient and to support optimal

mitochondrial function my wife and I

take magnesium breakthrough daily unlike

some supplements offering limited forms

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support do the mitochondria and the

different tissues

produce are they different I mean do

they work in different ways and do they

produce different

peptides absolutely and I think it's not

really appreciated even by many

scientists that the mitochondria from

say brain and liver and muscle are very

very different they look different by

electron microscopy if you isolate

mitochondria and do a proteomic analysis

you see very different distribution of

uh proteomic uh uh results if you look

at the function they're quite different

in their energetic profile so uh it's no

surprise that we identify different

profiles of expression of mitochondrial

peptides one of the techniques that

we've recently developed is the

mitochondrial equivalent of what's known

as RNA seek RNA seek is a technique that

was developed to measure the RNA from

tissue samples and look at all the

20,000 genes that Express RNA and

eventually proteins and see what goes up

and what goes down in various

conditions the standard RNA seek does

not look at microproteins certainly not

in the mitochondria and we've developed

a method to specifically analyze the

expression of mitochondrial peptide that

the RNA level and they're very different

from tissue to tissue and it's very

sensitive to uh disease States and

interventions of all sorts and um indeed

uh uh the profile of mitochondrial

peptide that are produced by

mitochondria from different tissue is

very

different interesting yeah I because I

always sort of mitochondria is being the

same like everywhere kind of like

standard issue you stick them in cells

and they just make energy but it's not

the

case that's interesting

yes there's a concept of mitochondria

transplant right so you can take

mitochondria and put them into uh

tissues and you know taking them from

one type of tissue to another can have

profound effects it's still a concept

that is in development and it's not

quite ready for you know even clinical

trials but um which mondria you start

with is going to have a major effect on

the results you're going to

get one question on mitochondria and

aging so do does the DNA damage in a

mitochondria just accumulate and

accumulate like over our whole a our

whole lifespan or do they have like I

don't know can they reset right so the

mitochondri employ a very different

model than normal Maman cells they are

essentially continue to function the way

unicellular bacterial like organism do

they divide much more first of all a

cell has two chromosomes uh two sets of

chromosomes and one cell and the cell

divides as needed in the tissue but each

cell has hundreds potentially thousands

of

mitochondria and the mitochondria divide

in an

asynchronous fashion with the rest of

the

cell and um there are many mitochondria

and they undergo a process known as

mitophagy which is kind of like

autophagy where a whole cell gets sort

of

eliminated uh when it it's done with its

role poorly functioning or sort of not

quite uh 100% effective mitochondria

gets eliminated through the concept of

mitophagy and even though we said that

there's a lot of damage that uh happens

to mitochondria as you age a lot of

these less than perfect mitochondria get

eliminated through this mitophagy

process

so you're always going to have some

functioning mitochondria but if you're

you know 18 your body is really good at

getting rid of all the abnormal

mitochondria and keeping like a really

good cohort of fully functioning

mitochondria but a time you reach my age

you know there are more and more of

these sort of semif functional ones that

are trying to do the job uh by the time

you get to 100 there's even less quality

control there um and you know that that

happens at a steeper rate than some

other uh components of the cell all of

which age but mondria seem to age

fastest among the different uh elements

in the

body how do the mitochondria change with

age and kind of what are the driving

factors

but push them so yeah so again it's it's

a it's a complex matter I mean in sense

that mitochondria very complex and

dynamic organ and and and they let's say

what happens normally the way that they

maintain ostasis is that they are

constantly generated and replaced

essentially um depending on the stimuli

and the uh metabolic inputs that I get

and the needs of the cells so and again

as I mentioned also before the way to

Main mitochondri mesis is either through

generating new mitochondria so

mitochondri bi bio biogenesis or

mitophagy in order to clear damage

mitochondria and also mitochondria

Dynamics are very important for this

because essentially mitochondria are can

be either fragmented and become like

more isolated and so on and this is when

they for instance can be taken up if

they are damaged to to be uh degraded by

mitophagy or they can be forming very

extensive networks to actually improve

or become more efficient in terms of

metabolic function so this normally

works uh very well and it's very Dynamic

and they can adapt very quickly in a

youthful or healthy status however over

time what happens is that due to the

decline also or in the other Pathways

that take care of things like

mitochondrial clearance uh loss of you

know let's say autophagy or other

Pathways that should be taken care of

reducing the damag mitochondria and the

fact that also mitochondria function in

terms of generation the energy so the

balance between the different complexes

within the mitochondria that would

generate ATP becomes altered due to

again um alteration of protein synthesis

uh reduced mitochondri biogenesis and so

on then the mitochondri start becoming

Also let's say less function in terms of

generating energy they may generate

perhaps more Ross and more oxidative

stress and they tend to accumulate also

so because they cannot be removed any

more efficiently through mitophagy

during aging due to the decline in this

process and so what happens is that you

tend to accumulate dysfunctional

mitochondria which then in term you know

they can start generating damage also

within the cells right because if you

have essentially more oxidative stress

and uh let's say less uh energy

generation and the inability to remove

this mitochondria essentially there will

be uh yeah that's when essentially

problems start occurring because then

you get an influence on the other all

marks as well so these all marks are

connected right so that's where it

becomes important to maintain om stasis

so how do we how do we encourage

mitophagy so uh yeah I mean from there

are several genetic uh Pathways that

modulate and mitophagy I mean in terms

of you know essentially that can be also

stimulated through let's say nutrient

sensing I mean there is uh the

involvement for instance of

phosphorilation processes that sense and

detect damaged mitochondria and then

they stimulate the ubiquity imp protome

system essentially uh to remove this

this so they attack the damage

mitochondria and then they recruit the

ubiquity imp protome system in order to

uh get rid of them pharmacologically

speaking there is I would say people are

actively looking to ways to specifically

Target mitophagy but I would say at the

moment perhaps one of the molecules that

I think it's very well known also in the

supplement space and so is tin a so that

one it's a natural molecule it's grass

recog oriz as generally U safe it's been

already used in humans a lot by um

essentially it's been discovered in my

ex Lab at epfl with the in the overx lab

and is now been used currently um um by

companies to do clinical trials and that

one seems to very strongly promote

mitophagy in several tissues and in

particular seems to work pretty well for

brain and muscle So preclinically

speaking with some initial evidence now

going for muscle aging in humans so that

one seems the most promising at the

moment yeah

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