This file contains the lectures and the cases from the first year that this course was provided. I included comments from the tutor that were provided during the tutorials. I also added the main points of all the papers discussed during the journal clubs (only briefly). In addition, it contains my ...
MBS1002 Biomedical approaches
This file contains the lectures and the cases from the first year that this course was provided. I
included comments from the tutor that were provided during the tutorials. I also added the main
points of all the papers discussed during the journal clubs (only briefly). In addition it contains my
presentation on the journal club about the hallmarks of ageing as well as my pitch on Q10.
Table of contents
Case 1 lipids in cancer ............................................................................................................................................. 2
Case 2 Novel Alzheimer’s drug .............................................................................................................................. 13
Case 3 Ageing immune system ............................................................................................................................. 22
Case 4 Of kimchi and relaxed DNA ........................................................................................................................ 33
Case 5 Cellular senescence ................................................................................................................................... 41
Case 6 Mitochondrial ageing ................................................................................................................................. 52
Lecture 1 Lipid detection in ageing ....................................................................................................................... 60
Lecture 2 Intervening in ageing ............................................................................................................................. 70
Lecture 3 Pathophysiology of Alzheimer’s disease ............................................................................................... 78
Lecture 4 Immunoageing ...................................................................................................................................... 87
Lecture 5 Genetics of ageing ................................................................................................................................. 96
Lecture 6 Cellular senescence ............................................................................................................................. 108
Lecture 7 NAD metabolism ................................................................................................................................. 114
Paper 1: Mass spectrometry imaging to detect lipid biomarkers and disease signatures in cancer .................. 116
Paper 2: Cardiolipins Are Biomarkers of Mitochondria-Rich Thyroid Oncocytic Tumors ................................... 119
Paper 3: ‘Evolutionary medicine’ perspectives on Alzheimer’s Disease: Review and new directions ................ 121
Paper 4: Transcranial Magnetic Stimulation in Alzheimer’s Disease: Are We Ready? ........................................ 123
Paper 5: Presentation on: Molecular and biological hallmarks of ageing ........................................................... 125
Paper 6: Metabolic Alterations in Aging Macrophages: Ingredients for Inflammaging? .................................... 130
Paper 7: NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome ............. 131
Paper 8: Current perspectives on the cellular and molecular features of epigenetic ageing ............................. 132
Paper 9: The metabolic roots of senescence: mechanisms and opportunities for intervention ........................ 133
‘Paper’ 10: Healthy aging and muscle function are positively associated with NAD+ abundance in humans .... 137
Paper 11: Impact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and
physical function ................................................................................................................................................. 141
Pitch on Q10 ........................................................................................................................................................ 143
,Case 1 lipids in cancer
Learning goals:
1. Lipid composition in membranes and how can you study them?
Lipids in membranes
Membrane lipids are the least studied biomolecules. First, the tools for the study of lipids are not as
powerful as the tools used for investigating genes and proteins. Second, lipids occur in membranes in
the form of ensembles, including around tens of thousands of individual members, which in turn are
representative of a variety of hundreds of different molecular species. Third, the high plasticity and
flexibility of biological membranes allow them to maintain their bioactivity despite the effect of
external insults. Nonetheless, cells depend upon lipids for three main functions, namely energy
storage, compartmentalization and signaling:
- Energy storage: lipid droplets used for this function contain mainly triacylglycerol and steryl
esters thanks to their relatively reduced state. These anhydrous reservoirs are needed for the
efficient storage of caloric reserves and as stores of fatty acid and sterol components for
membrane biogenesis.
- Compartmentalization: the milieu of cellular membranes is made of lipids of amphipathic
nature, comprising both a hydrophobic and a hydrophilic portion. This amphipathic nature
provides the physical basis for spontaneous membrane formation because the hydrophobic
moieties are prone to self-associate when dissolved in water. This predisposition to self-
associate enabled the segregation of an internal milieu from the external milieu when the
first cells originated. Later on, this scheme was repeated inside the cell to generate discrete
organelles allowing, first, the separation of specific chemical reactions, second, the limitation
in the spreading of reaction products and, third, an improvement in biochemical efficiency.
Furthermore, lipids are responsible of membrane ability of budding, tubulation, fission and
fusion, all them indispensable for cell division, biological reproduction and intracellular
membrane trafficking.
- Signaling: in signal transduction, lipids first define membrane domains that allow the
aggregation and dispersion of particular proteins, and subsequently organize secondary
signaling or effector complexes; they can also act as first and second messengers. The
rupture of amphipathic lipids generates bipartite signaling elements, which can be spread
both within a membrane (by hydrophobic portions of the molecule) and through the cytosol
(by soluble/polar portions of the molecule).
Phospholipids (PL) constitute the bulk of the membrane’s lipid matrix. They resemble the
triglycerides in being ester or amide derivatives of glycerol (glycerophospholipids, GPL) or
sphingosine (Sph –sphingolipids, SL) with fatty acids and phosphoric acid.
,Glycerophospholipids (GPL) are the major structural lipids in eukaryotic membranes. They are
generally composed of two fatty acids linked through two hydrophobic acyl chains and a phosphate
head group ester linked to a glycerol.
- In GPL, the phosphate moiety of the resulting phosphatidic acid is further esterified with
choline, ethanolamine, serine or inositol in the phospholipid itself.
- Therefore, GPL branch from phosphatidic acid (PA) and are classified upon the structure of
the PL head group. Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn)
heads are zwitterionic, whereas phosphatidylserine (PtdSer) and phosphatidylinositol
(PtdIns) heads are anionic.
- Each of these phospholipid classes is defined by a shared structure but then includes a
battery of molecular species upon the length and degree of saturation in their acyl chains.
Both head group and acyl chain composition influence the physical properties of the
membrane.
Sphingolipids (SL) are the second most abundant structural lipid. SL contain one hydrophobic acyl
chains and a phosphate head group ester linked to a Sph backbone. Their hydrophobic backbone is
an ester or amide derivative of Sph with fatty acids being ceramide (Cer) the simplest representative.
Sphingomyelin (SM) contains a phosphorylcholine headgroup associated to the sphingoid base.
- SM is the more abundant SL in the plasma membrane (PM) of mammalian cells. Within the
total PL fraction of the PM, SM accounts for 2%–15% upon the cell type.
- Other SLs are glycosphingolipids (GSLs). GSLs are based on glucosylceramide (GlcCer) or on
galactosylceramide (GalCer) and contain mono-, di- or oligosaccharides.
GPL and SL generate comparable series of messenger lipids upon signaling-induced hydrolysis.
- GPL hydrolysis produces the messenger lipids: lysoPtdCho (LPC), lysoPA (LPA), PA and
diacylglycerol (DAG).
- Whereas SL hydrolysis produces the messenger lipids: sphingosylphosphorylcholine (SPC),
Sph, sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P) and Cer (reviewed in [16]).
Cholesterol (Chol) is a crucial element of mammalian cell membranes. Chol molecule involves four
fused rings (steroid backbone) showing a hydroxyl group (A-ring) and a small branched hydrophobic
tail (D-ring).
- In membranes, the rigid steroid backbone of Chol favors its interaction with SL. Chol-SL
platforms are the basic element of lipid rafts.
- Chol content is strictly controlled by three mechanisms: de novo synthesis, uptake and
esterification.
, Lipids are distributed heterogeneously in several ranges: subcellular organelles show varied lipid
arrangements, furthermore PM and organelle membranes present foci of specific lipid domains, and
finally lipid distribution shows lateral differences and/or transversal asymmetry, i.e., asymmetric
distribution in both membrane leaflets.
The ER: the main site of lipid synthesis
The ER produces the bulk of the structural PL and Chol, together with significant levels of
triacylglycerol and cholesteryl esters with non-structural roles.
- In addition, the ER produces Cer, which is the precursor for complex SL. In the ER of
myelinating and epithelial cells GalCer is produced to stabilize myelin and apical membranes.
- Chol in the ER is only about 1%–2% of total Chol because, right after being synthesized, Chol
is transferred from the ER to the PM.
- The fast transport of Chol and other lipids to other organelles causes a loose arrangement of
membrane lipids in ER membrane. This loose lipid organization is critical for ER function as it
eases the insertion and the transport of recently synthesized lipids and proteins.
- Furthermore, the ER is the main supplier for a large percentage of membrane lipids in the
Golgi and PM, which are distal secretory organelles with restricted or null capacity to
produce their own lipids.
- In addition, the ER includes minor lipids known to be both pathway intermediates and
legitimate pathway end products (including DAG, cytidine diphosphoDAG, PA,
lysophospholipids) and dolichol.
- Finally, a subfraction of the ER, that cofractionates with mitochondria and is known as the
mitochondria-associated membrane, is particularly enriched in specific lipid biosynthetic
enzymes.
The Golgi apparatus: a lipid-based sorting station
Mammalian Golgi is the main producer of SL: SM, GlcCer, lactosylceramide (LacCer) and higher-order
GSLs, whose final destination is the PM.
- For SL production in the lumen of the trans-Golgi, Cer issued by the ER is required. Later on,
SL will accumulate in the PM whereas SL levels in the ER will be low. As it happens with SL,
sterols are scarce in the ER, representing only 5 mol% of lipids, in contrast to the trans-Golgi
and PM where sterols are abundant (30 mol%–40 mol%).
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