invecchiamento e fragilità: il contributo della metabolomicaaging, frailty and age-related diseases...

Invecchiamento e fragilità:il contributo della metabolomica

Roberta Pastorelli

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano

Metabolomics Definitions

Invecchiamento e fragilità: il contributo della metabolomicaRoberta Pastorelli/ Istituto Mario Negri IRCCS, MIlano

Metabolites are bio-active small molecules involved in the biochemical

network with a molecule mass less than 1 KDa in size Primary metabolite (endogenous) is directly involved in the normal growth,

development, and reproduction ( e.g. Sugars, Nucleosides, Amino acids,

Lipids)

Secondary metabolite (exogenous) is not directly involved in those processes,

but usually has important ecological function ( e.g. drug, gut microbiota)

Metabolome represents the collection of all metabolites in a given

biological sample

Metabolomics is the systematic identification and quantitation of the

metabolites fingerprint of a biological sample

‘-OMICS’ sciences

Environment (lifestyle, drug, diet, age, gender…)

The Metabolome does not exist in isolation

Invecchiamento e fragilità: il contributo della metabolomicaRoberta Pastorelli/ Istituto Mario Negri IRCCS, MIlano 4

Metabolomics: A Biological Integrator

An individual’s metabolic fingerprint

reflects alterations in homeostasis that

underlie health, disease and response.

This fingerprint is also a key tool for

understanding health influences that

operate by changing metabolism,

including:Genetics/Microbiota/Environm

ent/Diet/Epigenetics/Combined effects

Measuring metabolites offers functional understanding of complex biological processes

Given metabolites’ proximity to the phenotype, metabolomics is an important tool

for unlocking the full potential of disease research, genomics and precision

medicine.

Metabolome Complexity

Metabolic pathways do not exist in isolation

Metabolome Complexity

Metabolites Can Appear in Multiple Pathways

One technology – many applications

Not only does metabolomics allow

to extract value from other types of

“omics data”, it can be used to

discover biomarkers, track

treatment effects etc.

And, because the metabolite

composition is central to every

living organism, the in-depth

biological insights metabolomics

provides can advance research

across a variety of areas.:

Metabolomics strategies

Metabolism and Aging

Basic concept in metabolism

The big picture

glycolysis - glucose oxidation in order to

obtain ATP

gluconeogenesis - glucose synthesis

from smaller percursors, to be used by

the brain.

citric acid cycle (Krebs' cycle) - acetyl-

CoA oxidation in order to obtain GTP and

valuable intermediates.

oxidative phosphorylation - disposal of

the electrons released by glycolysis and

citric acid cycle. Much of the energy

released in this process can be stored as

urea cycle - disposal of NH4+ in less toxic

fatty acid β-oxidation - fatty acids

breakdown into acetyl-CoA, to be used

by the Krebs' cycle.

gluconeogenesis - glucose synthesis

from smaller percursors, to be used by

the brain.

The Seven Pillars of Aging

Hallmarks of aging

Mechanistics hallmarks that contribute to ageing to different extents and in

different cells types within an organism. from Lopez-Otin C et al Cell, 2016

Metabolism and Epigenetic alteration

Metabolic control of histone methylation

GENE EXPRESSION

Metabolism & Deregulated nutrient sensing

Invecchiamento e fragilità: il contributo della metabolomicaDott. Roberta Pastorelli/ Istituto Mario Negri IRCCS, MIlano

Metabolic sensors

mTOR (aminoacids)

AMPK (ADP/AMP) Sirtuins (NAD+/NADH)

Metabolism & mitochondrial dysfunction

TCA cycle decreased efficiency

Inadeguate TCA cycle intermediates

Respiratory chain defects due to

enzyme/substrate alterations

………

from Rustin et al., Mech Age Develop 2000

Aging, frailty and age-related diseases

Frailty is a nonspecific state of vulnerability, which

reflects multisystem physiological change

Interrelation between aging and diseases leading to

the development of frailty.

“There is a strong interrelation between

the biological aging changes and the development of

age-related diseases.

The interface could be the development of the-frailty

syndrome.

Besides this intersection, either the biological

aging or the age-related diseases can lead to the

frailty-syndrome characterized by the clinically

apparent changes leading to catastrophic

consequences».

From Fulop et al., 2010.

The need of multidimensional approach

Literature overview of the termsmetabolomics/metabolome and frailty/frail

2 0 0 0 2 0 0 2 2 0 0 4 2 0 0 6 2 0 0 8 2 0 1 0 2 0 1 2 2 0 1 4 2 0 1 6 2 0 1 8

(PubMed)

Metabolomics

frailty

Metabolomics & Frailty

Plasma aminoacids & Frailty

Circulating aminoacids trajectories linked to malnutrition (both quantitative

and qualitative), a common causative factor of frailty and sarcopenia

From Calvani R et al , 2018

From Sun L et al., 2017

Muscle metabolome & Frailty

The major differences in muscle

metabolome of frail older subjects to

healthy older subjects relate to

mitochondrial function,

fiber-type composition

tissue turnover

BCCA correlate with genes related to

connective tissue/extracellular matrix

(SPARC)

From Fazelzadeh P et al 2016

Pre-frailty Metabolomic sub-phenotypes

Metabolomics allowed discriminating

metabolic sub-phenotypes of pre-frailty

both at the gender level and depending on

the pre-frailty progression and reversibility,

with the identification of specific circulating

discriminant metabolites.

From Pujos-Guillot et al., Frontiers in Physiology, 2019

“In the stable population, pipecolic acid, proline, butyrylcarnitine,

and lysoPEs were found significantly upregulated in pre-frail

men, whereas in women, most of the significant metabolites were

found down regulated. In the group of subjects who will improve

their frailty status (Improvement), the most significant modulated

metabolites are amino acids and derivatives, as well as sugars”

..still many questions

Organs influence each other's function via multiple mechanisms including

endocrine signaling, thereby influencing metabolism and ageing in a non-

autonomous fashion.

How do nutrition, exercise and related signaling pathways affect

ageing and frailty?

What metabolites affect ageing (e.g. immune system function) and

frailty/frailty progression?

Are gender differences in frailty affecting metabolome signatures?

Metabolomics & frailtuning

Unit of Proteins and Metabolites Biomarkers,

Lab of Mass Spectrometry

Istituto di Ricerche Farmacologiche Mario Negri IRCCS,

Milano

Metabolomics & frailtuning

WP2. Biomarker assessmentTask 1. Analysis of participants’ metabolic profile

identification of metabolic phenotypes related to

the concept of frailty

The plasma metabolomic profiling are performed by a

targeted mass spectrometry-based quantitative

approach that allows the simultaneous identification

and quantitation of approx. 200 circulating

metabolites spanning over 6 metabolic classes

(acylcarnitines, aminoacids, biogenic amines,

glycerophospholipids, sphingolipids, sugars).

Metabolomics & frailtuningList of the measurable metabolites

Metabolomics & frailtuningPreliminary metabolomic results

✓ Frail subjects are separated from pre- and non-

frail subjects mainly by different levels of

aminoacids (increased trend in Fr) and long-

chain diacyl-phosphatidylcholines (PCaa)

(decreased trend in Fr)

✓ Analyses on larger number of subjects and

longitudinal cohort are ON-GOING

Challange and Hope

define unifying metabolic escape principles that would be suitable to reset metabolism as a means to prevent frailty

invecchiamento e fragilità: il contributo della metabolomicaaging, frailty and age-related diseases...

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