Ageing Research Reviews: A B C D e F C D e

Ageing Research Reviews 60 (2020) 101070
Contents lists available at ScienceDirect
Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr
Systematic review and analysis of human proteomics aging studies unveils a T

novel proteomic aging clock and identifies key processes that change with
age
Adiv A. Johnsona,*, Maxim N. Shokhirevb, Tony Wyss-Corayc,d,e,f, Benoit Lehallierc,d,e
a
Nikon Instruments, Melville, NY, United States
b
Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, CA, United States
c
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
d
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
e
Paul F. Glenn Center for the Biology of Aging, Stanford University, Stanford, CA, United States
f
Department of Veterans Affairs, VA Palo Alto Health Care System, Palo Alto, CA, United States
ARTICLE INFO ABSTRACT
Keywords: The development of clinical interventions that significantly improve human healthspan requires robust markers
Aging of biological age as well as thoughtful therapeutic targets. To promote these goals, we performed a systematic
Lifespan review and analysis of human aging and proteomics studies. The systematic review includes 36 different pro-
Proteomics teomics analyses, each of which identified proteins that significantly changed with age. We discovered 1,128
Biomarkers
proteins that had been reported by at least two or more analyses and 32 proteins that had been reported by five
Longevity
or more analyses. Each of these 32 proteins has known connections relevant to aging and age-related disease.
Healthspan
GDF15, for example, extends both lifespan and healthspan when overexpressed in mice and is additionally
required for the anti-diabetic drug metformin to exert beneficial effects on body weight and energy balance.
Bioinformatic enrichment analyses of our 1,128 commonly identified proteins heavily implicated processes
relevant to inflammation, the extracellular matrix, and gene regulation. We additionally propose a novel pro-
teomic aging clock comprised of proteins that were reported to change with age in plasma in three or more
different studies. Using a large patient cohort comprised of 3,301 subjects (aged 18–76 years), we demonstrate
that this clock is able to accurately predict human age.
1. Introduction there is a strong imperative to develop therapies that can mitigate age-
related disease and prolong the period of healthy life.
Powerful insights into the mechanisms of aging (Singh et al., 2019) The development of such interventions can be theoretically ac-
and the development of strategies that extend lifespan and improve celerated by aging clocks, which are a set of molecules capable of
health in animals (Mahmoudi et al., 2019) have given rise to a plethora predicting patient age (Ferrucci et al., 2019). These clocks are ad-
of anti-aging biotech companies seeking to elongate human healthspan vantageous because they can provide specific information about the
(Campisi et al., 2019; de Magalhaes et al., 2017). The discovery that internal health of an individual (i.e., biological age) rather than gen-
centenarians frequently achieve exceptional longevity with minimal eralized health information associated with a particular age range
disease and a lower prevalence of comorbidities compared to non- (Johnson and Stolzing, 2019). Anti-aging clinical interventions in hu-
centenarians (Ailshire et al., 2015; Gellert et al., 2018) suggests that mans could therefore be tested by assessing the effect of a therapy on
such a goal is feasible. Since age-related diseases represent leading biological age rather than chronological lifespan. Numerous different
causes of mortality and healthcare costs, the successful development of aging clocks have been reported in the literature, including epigenetic
treatments that promote healthy aging has transformative implications (Horvath and Raj, 2018), transcriptomic (Fleischer et al., 2018; Peters
for society (de Magalhaes et al., 2017). In the meantime, the complex et al., 2015), and proteomic (Lehallier et al., 2019) predictors of human
social and medical costs presented by biological aging are continually age. In a recent study, individuals who were predicted to be younger
rising and represent an ever-growing challenge (Rae et al., 2010). Thus, than their chronological age performed better on cognitive and physical
⁎
Corresponding author.
E-mail address: [email protected] (A.A. Johnson).
https://doi.org/10.1016/j.arr.2020.101070
Received 31 January 2020; Received in revised form 23 March 2020; Accepted 7 April 2020
Available online 18 April 2020
1568-1637/ © 2020 Elsevier B.V. All rights reserved.
A.A. Johnson, et al. Ageing Research Reviews 60 (2020) 101070
tests (Lehallier et al., 2019). Epigenetic clocks have also been utilized to and the tissues and/or cell types where the protein was reported.
demonstrate that age-related disease is associated with a higher biolo-
gical age relative to chronological age, a phenomenon referred to as 2.3. Literature test of relevance to aging and age-related disease of the most
epigenetic age acceleration (Horvath and Raj, 2018). While existing commonly reported proteins
estimators of patient age show incredible utility, this is a nascent field
and it is likely that these aging clocks can be further optimized. For the most common proteins that were reported to significantly
The high cost and time investment required to complete an effective change with age by five or more different analyses, we performed a
anti-aging clinical trial (de Grey, 2019) also necessitates the selection of literature search to determine if there were any relevant publications
thoughtful therapeutic targets. In order to help optimize aging clocks indicating a role relevant to aging or age-related disease. This included
and identify high-potential targets for anti-aging clinical trials, we un- looking up proteins in Human Ageing Genomic Resources (de
derwent a systematic review and analysis of human proteomics and Magalhaes et al., 2009; Tacutu et al., 2018) as well as utilizing PubMed
aging studies. More specifically, we analyzed studies which reported a and Google to search for a protein name in conjunction with the key-
set of proteins that significantly changed their expression level with words “aging”, “disease”, “lifespan”, “life span”, “healthspan”, “health
human age. We chose to focus on proteins as these represent functional span”, or “longevity”.
products and because transcriptomic changes don’t always correlate
with proteomic changes (Bathke et al., 2019; Haider and Pal, 2013). 2.4. Bioinformatics analyses of commonly identified proteins that change
Since different proteomics and aging studies have utilized different with human age
proteomics techniques, patient populations, statistical analyses, tissues,
and cell types, it is unsurprising that their findings significantly vary UniProt (UniProt, 2019) gene IDs of 1,128 age-associated proteins
from one another. These findings are, for example, notably disparate identified in two or more different studies or gene IDs of the 32 most
even when the same biofluid is analyzed (Lehallier et al., 2019; Menni commonly identified proteins were tested for overrepresentation among
et al., 2015; Tanaka et al., 2018; Tin et al., 2019). Consequently, our known pathways from KEGG (Kanehisa and Goto, 2000) Release 88.2,
aim was to identify common proteins that were reported to significantly Reactome (Jassal et al., 2020) v66, the non-redundant Gene Ontology
change with age by multiple different studies. We theorized that such (GO) (The Gene Ontology, 2019) Biological Process (BP) accessed on 1/
common proteins would have a higher likelihood of being relevant to 6/2020, WikiPathways (Slenter et al., 2018) Release 11/10/2018, and
human aging. GLAD4U (Jourquin et al., 2012) accessed on 1/6/2020. These databases
In this study, we identify a large set of common proteins that have were analyzed using WebGestalt (Liao et al., 2019) with a minimum
been reported to change with human age in two or more different aging number of IDs in a category set to 3, maximum number of IDs in a
analyses. We uncover a smaller number of especially common proteins category set to 1000, all protein coding genes as the background, and
that we propose are viable candidates for anti-aging clinical trials and/ FDR < 0.05 as the cutoff. The weighted set cover was used to find the
or aging biomarking. We additionally perform bioinformatics enrich- top 10 gene sets while maximizing gene coverage. The 32 most com-
ment analyses to unveil which pathways and processes are implicated monly identified proteins were also subject to WebGestalt Network
by our common proteins. Lastly, we propose and fully validate a novel Topology-based Analysis (NTA) using the BioGRID (Oughtred et al.,
proteomic aging clock comprised of plasma proteins identified in the 2019) build 3.5.167 database to expand the network to include the top
systematic review. 50 neighbors. This was followed by the identification of the top 10
significant GO BP terms.
2. Methods
2.5. Generation of a plasma protein panel for aging biomarking
2.1. Identifying human proteomics and aging studies for the systematic
review To establish a proposed panel to be used for aging biomarking in
plasma, we first compiled a list of all proteins that had been reported to
To be considered for inclusion in the systematic review, a study had change significantly with age in plasma by four or more different stu-
to explicitly discover a set of proteins that significantly change with age dies. An online aging plasma proteome interface created by Lehallier
in humans. These studies were predominantly found by searching for et al was utilized for validation testing of the suggested markers
the following combinations in PubMed and Google: “aging” and “pro- (Lehallier et al., 2019). This resource was used to measure the p-value
teome”, “aging” and “proteomic”, “aging” and “proteomics”, “age” and and q-value as well as to assess the expression trend over time in a
“proteome”, “age” and “proteomic”, “age” and “proteomics”, “lifespan” plasma proteomic dataset from 4,263 healthy individuals spanning an
and “proteome”, “lifespan” and “proteomic”, and “lifespan” and “pro- age range of 18–95 years. For the “Regression line” and “Subset” op-
teomics”. The PRIDE archive was also perused for human studies that tions, “Loess” and “All” were chosen, respectively.
reported age information. This approach identified 32 different re-
search publications, including one article that performed analyses in 2.6. Testing of the plasma proteomic aging clock in a large patient cohort
five different bone marrow-derived cell types. Thus, a total of 36 ana-
lyses are included in the present systematic review. Proteomics measurements from 3,301 human plasma samples col-
lected during the INTERVAL clinical trial were used to test whether
2.2. Systematic review of human proteomics and aging studies commonly identified aging plasma proteins can predict chronological
age. Participants in the INTERVAL randomized controlled trial
Having collated 36 different aging analyses, we listed out all pro- (ISRCTN24760606) were recruited with the active collaboration of the
teins reported to significantly change with age in each study. Every National Health Service (NHS) Blood and Transplant, which has sup-
protein was manually checked to see if it conformed to the primary ported field work and other elements of the trial. DNA extraction and
gene name recommendation of UniProt (UniProt, 2019). If a protein genotyping were co-funded by the National Institute for Health
was identified to have a non-standard name, its name was changed to Research (NIHR), the NIHR BioResource, and the NIHR Cambridge
match the recommendation of UniProt. If a protein was identified in Biomedical Research Centre at the Cambridge University Hospitals NHS
two or more studies, that protein was highlighted in bold. These Foundation Trust. The INTERVAL study was funded by NHS Blood and
common proteins were then collated. For each common protein, the Transplant (11-01-GEN). The academic coordinating center for INTE-
following information was included: UniProt ID, the number of dif- RVAL was supported by core funding from the NIHR Blood and
ferent studies that reported the protein to significantly change with age, Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-
2
2014-10024), the UK Medical Research Council (MR/L003120/1), the 3.2. Identification of common proteins reported by two or more studies to
British Heart Foundation (RG/13/13/30194), and the NIHR Cambridge significantly change with age in humans
Biomedical Research Centre at the Cambridge University Hospitals NHS
Foundation Trust. Proteomic assays were funded by the academic co- Having identified the studies for inclusion in our systematic review,
ordinating center for INTERVAL and Merck Research Laboratories we then made a table that included proteins reported to significantly
(Merck & Co., Kenilworth, New Jersey, United States). A complete list change with age in each study (Supplementary Table 1). We were
of the investigators and contributors to the INTERVAL trial was pre- surprised to find that a large number of proteins – specifically 1,128
viously reported (Di Angelantonio et al., 2017). The academic co- proteins – were reported by at least two or more different analyses
ordinating center would like to thank blood donor center staff and (Supplementary Table 2). While many proteins were unique to a single
blood donors for participating in the INTERVAL trial. tissue – such as IGFBP6 and TNFRSF11B, both of which were reported
Participants were healthy and age ranged from 18 to 76 years with a in plasma by four different studies (Supplementary Table 2) and both of
median age of 45 years (first quartile = 31; third quartile = 55). which significantly increase with age (Lehallier et al., 2019) – we were
Sample selection, processing and preparation were detailed previously also surprised by the amount of tissue overlap for some proteins. Ex-
(Sun et al., 2018a). We tested two different clocks including plasma emplar of this, the heat shock protein HSPB1 was reported to change
proteins reported in either 3+ or 4+ studies. Of the included 85 with age in skeletal muscle, liver, colon, and skin (Supplementary
plasma proteins identified in 3 or more studies, 83 proteins were Table 2). Similarly, the protein ANXA1 was found to change with age in
measured by 103 SOMAmers in this version of the SOMAscan assay. plasma, skeletal muscle, saliva, skin, and tear fluid (Supplementary
The 23 plasma proteins identified in 4 or more studies were measured Table 2). Of the 1,128 common proteins we identified, 751 (66.58 %)
by 27 SOMAmers. Linear models were used with z-scaled log10–- were reported in two or more different tissues and/or cell types. Only
transformed relative fluorescence units (RFUs) as input. Two-thirds (n 377, or approximately 1/3 (33.42%) were reported in a single tissue or
= 2,178) of the samples were used for training the model and the re- cell type (Supplementary Table 2).
maining 1,123 samples were used as a validation.
3.3. Many common proteins have previously reported connections to aging
3. Results A number of these common proteins have prominent aging con-

nections. For example, the protein APOE was reported a total of three
3.1. Collation of 32 different papers and 36 different analyses for the times – once in plasma, once in cerebrospinal fluid, and once in serum
systematic review (Supplementary Table 2). Meta-analyses have firmly established that
genetic variants of APOE are significantly linked with human longevity
As discussed in the Methods, we first performed a detailed literature (Deelen et al., 2019) and late-onset Alzheimer’s disease (Kunkle et al.,
search to find studies that identified a set of proteins which significantly 2019). Another example is GDF11, which significantly changed with
change their expression level during human aging. This search revealed age in plasma in two different studies (Supplementary Table 2). In mice,
32 different papers, including one paper that performed proteomic this circulating blood factor declines with age, is restored via hetero-
aging analyses on five different bone-marrow derived cell types chronic parabiosis, and has been reported to mediate numerous re-
(Table 1). Thus, the systematic review included a total of 36 different juvenative functions when given exogenously (Mahmoudi et al., 2019).
aging analyses. The age range spanned from neonatal (< 1 year old) to GDF11 also declines with age in human plasma (Lehallier et al., 2019).
95 years old. The number of patients utilized in each study varied no- While this protein is worthy of additional exploration, it is important to
tably, ranging from 6 to 4,263. Adding up the N number for each of the note that the beneficial effects of GDF11 have not been consistently
32 references yields a value of 11,225. While LC–MS/MS was the most reported (Mahmoudi et al., 2019). IGF1 was reported twice, once in
popular proteomics technique used, several papers made use of the plasma and once in cerebrospinal fluid (Supplementary Table 2). This is
newer SOMAscan assay. 2D gel electrophoresis was also employed by noteworthy as inhibition of the insulin-IGF1 signaling pathway is one of
some research groups, but this was more common among older papers the most established and evolutionarily conserved life extension stra-
and was not seen in included work published after 2012. Other tech- tegies (Singh et al., 2019). Mutations in the gene LMNA cause the ac-
niques, such as a proximity extension assay or SWATH-MS, were also celerated aging disease Hutchinson-Gilford Progeria Syndrome
used to discover proteins that significantly change with age (Table 1). (Gonzalo et al., 2017). LMNA was identified once in skeletal muscle and
These studies spanned a diverse set of tissues (Table 1), namely once in liver (Supplementary Table 2). Another example is the histone
blood (serum and plasma), skeletal muscle (vastus lateralis), liver, bone deacetylase SIRT5, which was reported twice in plasma and once in
marrow, saliva, cerebrospinal fluid, skin, colon (epithelial tissue), liver (Supplementary Tables 1 and 2). SIRT5 is a member of the larger
urine, olfactory cleft, tear fluid, and brain (frontal cortex). The fol- NAD+-dependent sirtuin family that has been intimately linked to
lowing cell types were also represented in the systematic review: me- aging and lifespan in animal models (Bonkowski and Sinclair, 2016).
senchymal stem / stromal cells (bone marrow-derived), lymphocytes Other examples include AKT2 (Supplementary Table 2), which has
and precursors (bone marrow-derived), monocytes / macrophages and been reported to prolong lifespan and improve myocardial function in
precursors (bone marrow-derived), granulocytic precursors (bone mice when ablated (Ren et al., 2017). AKT2 was identified in plasma by
marrow-derived), dermal fibroblasts (skin-derived), erythroid pre- two different studies (Supplementary Table 2). EFEMP1 was listed four
cursors (bone marrow-derived), T-cells (blood-derived), and B cell different times, thrice in plasma and once in urine (Supplementary
lymphocytes (blood-derived). Plasma was the most common tissue in- Tables 1 and 2). Knocking out this gene in mice reduces fecundity and
cluded and represented 10 of the 32 studies. Bone marrow is indicated induces multiple aspects of premature aging, including a shortened
five times, although each indication represents an analysis in a different lifespan, lordokyphosis, a smaller body mass, less hair growth, and
bone marrow-derived cell type. Serum, urine, and skeletal muscle generalized atrophy of fat, muscle, and organ (McLaughlin et al., 2007).
(vastus lateralis) are all represented three times while skin (dermal fi- The protein NNMT was reported once in skeletal muscle and once in
broblasts) and cerebrospinal fluid each appear twice. Liver, saliva, liver (Supplementary Table 2). In Caenorhabditis elegans, the nematode
colon (epithelial tissue), T cells (blood-derived), olfactory cleft, tear ortholog of this protein is required for sirtuin-mediated life extension.
fluid, B cell lymphocytes (blood-derived), and brain (frontal cortex) This enzyme is responsible for methylating nicotinamide to generate 1-
each make a single appearance. The number of identified proteins in- methylnicotinamide (Schmeisser et al., 2013), which is highly relevant
cluded in the present systematic review fluctuated from study to study to aging given that elevating NAD+ levels extends lifespan and
and ranged from 2 to 1,359 (Table 1). healthspan in mice (Rajman et al., 2018). Moreover, it has been
3
Table 1
Studies utilized in the proteomic human aging systematic review and analysis. Tissue and/or cell type, number of patients, age information, proteomics technique,
total number of proteins included that were reported to significantly change with age, and corresponding reference are all provided. Studies are sorted by the number
of proteins included (most to least).
Tissue and/or Cell Type N Age Range or Mean Age Proteomics Technique # of Proteins Reference
(Years)
Blood; plasma 4263 18-95 SOMAscan 1359 (Lehallier et al., 2019)

Skeletal muscle; vastus lateralis 58 20-87 LC-MS/MS 916 (Ubaida-Mohien et al., 2019)
Blood; plasma 42 45-∼84* SOMAscan 833 (Tin et al., 2019)
Liver 11 31-88 LC-MS/MS 719 (Heinze et al., 2018)
Blood; plasma 240 22-93 SOMAscan 216 (Tanaka et al., 2018)
Bone marrow; mesenchymal stem / stromal cells 59 20-60 LC-MS/MS 212 (Hennrich et al., 2018)
Saliva 20 19-89 LC-MS/MS 107 (Wang et al., 2018)
Bone marrow; lymphocytes and precursors 59 20-60 LC-MS/MS 102 (Hennrich et al., 2018)
Cerebrospinal fluid 90 21-85 SOMAscan 77 (Baird et al., 2012)
Blood; plasma 1016 70-80 Proximity extension assay 62 (Lind et al., 2019)
Bone marrow; monocytes / macrophages and 59 20-60 LC-MS/MS 53 (Hennrich et al., 2018)
precursors
Bone marrow; granulocytic precursors 59 20-60 LC-MS/MS 45 (Hennrich et al., 2018)
Skin; dermal fibroblasts 15 20-70 LC-MS/MS 43 (Waldera-Lupa et al., 2014)
Bone marrow; erythroid precursors 59 20-60 LC-MS/MS 37 (Hennrich et al., 2018)
Colon epithelial tissue 30 25-65 2D gel electrophoresis 35 (Li et al., 2007)
Cerebrospinal fluid 32 22-85 LC-MS/MS 33 (Zhang et al., 2005)
Blood; serum 157 3-25 Antibody bead array 30 (Signorelli et al., 2019)
Blood; T-cells 22 21-83 LC-MS/MS 29 (Bektas et al., 2019)
Blood; plasma 1005 ∼15-∼90** Proximity extension assay 24 (Enroth et al., 2014)
Skeletal muscle; vastus lateralis 12 20-76 2D gel electrophoresis 24 (Gelfi et al., 2006)
Urine 52 19-54 LC-MS/MS 24 (Pastushkova et al., 2016)
Urine 37 19-90 LC-MS/MS 24 (Bakun et al., 2014)
Skin; dermal fibroblasts ≥9*** ∼15-∼82*** 2D gel electrophoresis 23 (Boraldi et al., 2003)
Blood; B cell lymphocytes 6 25-83 LC-MS/MS 23**** (Mayer et al., 2018)
Olfactory cleft 24 21-80 LC-MS/MS 20 (Yoshikawa et al., 2018)
Blood; plasma 42 <1 - 43 2D gel electrophoresis 18 (Ignjatovic et al., 2011)
Blood; serum 187 18-77 SOMAscan 15 (Di Narzo et al., 2017)
Tear fluid 115 18-83 SWATH-MS 14 (Nattinen et al., 2019)
Skeletal muscle; vastus lateralis 8 47-82 2D gel electrophoresis 14 (Staunton et al., 2012)
Blood; plasma 206 65.30 SOMAscan 13 (Menni et al., 2015)
Blood; serum 36 23-91 2D gel electrophoresis 12 (Byerley et al., 2010)
Blood; plasma 1002 16-81 LC-MS/MS 9 (Cominetti et al., 2018)
Blood; plasma 1890 18-82 MALDI-TOF-MS 6 (Lu et al., 2012)
Urine 324 2-73 CE-MS/MS 5 (Zurbig et al., 2009)
Brain; frontal cortex 20 63-92 2D gel electrophoresis 4 (Muller et al., 2008)
Blood; plasma 195 ∼71***** Multiplex assay and single molecule 2 (Elahi et al., 2019)
array
*
Patients were assessed over multiple visits spanning a period of approximately 20 years.
**
This age range is estimated from the graph presented in Supplementary Fig. 2 of the study by Enroth et al (Enroth et al., 2014).
***
Three age groups were studied (15 ± 2, 41 ± 4, 82 ± 3) and three-four females in each age group were investigated.
****
These represent proteins that are significantly changed by both age and B cell chronic lymphocytic leukemia.
*****
Mean age estimated from the reported mean age for three different groups included in the analysis (controls, early-onset Alzheimer’s disease, late-onset
Alzheimer’s disease).
demonstrated that the NAD+ precursor nicotinamide riboside is well- were reported by two or more different studies (Supplementary
tolerated and can effectively boost NAD+ levels in humans (Martens Table 2), we found that there were 337 proteins reported by three or
et al., 2018). The related nicotinamide enzyme NAMPT was also re- more different studies (Supplementary Table 3) and 117 proteins that
ported twice in plasma (Supplementary Table 2). Supplementation of were reported by four or more different studies (Supplementary
this protein extends lifespan and enhances physical activity in aged Table 4). Only 32 proteins were reported by five more different studies
mice (Yoshida et al., 2019). The gene SHH, which encodes Sonic (Table 2), making these the most common proteins identified to change
hedgehog protein, was reported once in plasma and once in cere- with age in our systematic review.
brospinal fluid (Supplementary Table 2). In Drosophila melanogaster, the These 32 proteins, which are listed in Table 2, are as follows: serum
adult-specific depletion of this gene reduces lifespan while increased albumin (ALB), annexin A1 (ANXA1), annexin A2 (ANXA2), ATP syn-
expression results in life extension. Hedgehog signaling also regulates thase subunit beta, mitochondrial (ATP5F1B), complement C3 (C3),
proteostasis in fruit flies (Rallis et al., 2020). While this list is not ex- complement C4-A (C4A), calpain small subunit 1 (CAPNS1), collagen
haustive, it indicates that at least a portion of these common proteins alpha-1(XVIII) chain (COL18A1), collagen alpha-1(I) chain (COL1A1),
are not only viable aging biomarkers but are also potent regulators of cathepsin S (CTSS), epidermal growth factor receptor (EGFR), fi-
aging. brinogen alpha chain (FGA), fibrinogen gamma chain (FGG), fi-
bronectin (FN1), growth/differentiation factor 15 (GDF15), aspartate
aminotransferase, cytoplasmic (GOT1), glutathione S-transferase P
3.4. Identification of a small set of common proteins reported by five or (GSTP1), hepatocyte growth factor (HGF), heterogeneous nuclear ri-
more studies to change with age in humans bonucleoprotein D-like (HNRNPDL), haptoglobin (HP), laminin subunit
gamma-1 (LAMC1), prolow-density lipoprotein receptor-related protein
We next sought to determine which proteins were the most com- 1 (LRP1), macrophage metalloelastase (MMP12), protein/nucleic acid
monly reported to change significantly with age. While 1,128 proteins
4
Table 2
Age-associated proteins identified in five or more different studies. For each protein, the UniProt ID, the number of studies that reported the protein, and the relevant
tissues and/or cell types is provided. Proteins are organized alphabetically according to their gene abbreviation. A total of 32 proteins are listed.
Protein and Gene Names UniProt # of Studies Tissues and/or Cell Types Reported
Serum albumin (ALB) P02768 7 Liver, plasma, vastus lateralis, serum, tear fluid
Annexin A1 (ANXA1) P04083 6 Plasma, vastus lateralis, saliva, dermal fibroblasts, tear fluid
Annexin A2 (ANXA2) P07355 6 Plasma, vastus lateralis, liver, colon epithelial tissue
ATP synthase subunit beta, mitochondrial (ATP5F1B) P06576 5 Plasma, vastus lateralis, colon epithelial tissue, T cells
Complement C3 (C3) P01024 7 Plasma, liver, cerebrospinal fluid, serum
Complement C4-A (C4A) P0C0L4 5 Plasma, cerebrospinal fluid, serum
Calpain small subunit 1 (CAPNS1) P04632 5 Plasma, liver, lymphocytes and precursors, granulocytic precursors, dermal
fibroblasts
Collagen alpha-1(XVIII) chain (COL18A1) P39060 5 Plasma, vastus lateralis, cerebrospinal fluid
Collagen alpha-1(I) chain (COL1A1) P02452 6 Plasma, vastus lateralis, liver, mesenchymal stem / stromal cells, urine, serum
Cathepsin S (CTSS) P25774 5 Plasma, liver, mesenchymal stem / stromal cells, saliva
Epidermal growth factor receptor (EGFR) P00533 5 Plasma, vastus lateralis, cerebrospinal fluid
Fibrinogen alpha chain (FGA) P02671 7 Plasma, liver, cerebrospinal fluid
Fibrinogen gamma chain (FGG) P02679 6 Plasma, liver, saliva
Fibronectin (FN1) P02751 6 Plasma, mesenchymal stem / stromal cells, saliva, urine
Growth/differentiation factor 15 (GDF15) Q99988 5 Plasma
Aspartate aminotransferase, cytoplasmic (GOT1) P17174 7 Plasma, vastus lateralis, liver, frontal cortex
Glutathione S-transferase P (GSTP1) P09211 5 Plasma, colon epithelial tissue, olfactory cleft, dermal fibroblasts
Hepatocyte growth factor (HGF) P14210 5 Plasma, cerebrospinal fluid
Heterogeneous nuclear ribonucleoprotein D-like (HNRNPDL) O14979 5 Plasma, vastus lateralis, saliva, monocytes / macrophages and precursors
Haptoglobin (HP) P00738 8 Plasma, vastus lateralis, liver, saliva, cerebrospinal fluid, serum
Laminin subunit gamma-1 (LAMC1) P11047 5 Plasma, vastus lateralis, liver, serum
Prolow-density lipoprotein receptor-related protein 1 (LRP1) Q07954 5 Plasma, vastus lateralis, liver
Macrophage metalloelastase (MMP12) P39900 5 Plasma
Protein/nucleic acid deglycase DJ-1 (PARK7) Q99497 5 Plasma, liver, saliva, olfactory cleft, vastus lateralis
Urokinase plasminogen activator surface receptor (PLAUR) Q03405 6 Plasma, cerebrospinal fluid
Pleiotrophin (PTN) P21246 5 Plasma, cerebrospinal fluid
Serotransferrin (TF) P02787 5 Plasma, liver, saliva, vastus lateralis, tear fluid
Lamina-associated polypeptide 2, isoforms beta/gamma (TMPO) P42167 5 Plasma, vastus lateralis, liver, mesenchymal stem / stromal cells
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) P19438 6 Plasma, cerebrospinal fluid
Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) P20333 6 Plasma, cerebrospinal fluid
Triosephosphate isomerase (TPI1) P60174 6 Vastus lateralis, plasma, liver, colon epithelial tissue, dermal fibroblasts
Vascular endothelial growth factor A (VEGFA) P15692 5 Plasma, mesenchymal stem / stromal cells
deglycase DJ-1 (PARK7), urokinase plasminogen activator surface re- Interventions targeting other proteins in this list have also been
ceptor (PLAUR), pleiotrophin (PTN), serotransferrin (TF), lamina-as- reported to significantly extend animal lifespan. RNAi knockdown
sociated polypeptide 2, isoforms beta/gamma (TMPO), tumor necrosis against atp-2 (ortholog of ATP5F1B) in C. elegans (Chin et al., 2014) or
factor receptor superfamily member 1A (TNFRSF1A), tumor necrosis LRP1 and LRP2 in D. melanogaster (Brankatschk et al., 2014) is sufficient
factor receptor superfamily member 1B (TNFRSF1B), triosephosphate to boost longevity (Table 3). Similarly, a gain of function mutation in
isomerase (TPI1), and vascular endothelial growth factor A (VEGFA). let‐23 (worm EGF receptor) prolongs life in C. elegans (Iwasa et al.,
2010) and the overexpression of gst-10 (worm ortholog of GSTP1)
3.5. All proteins identified to change with age in five or more studies have (Ayyadevara et al., 2005) or pleiotrophin (Hugosson et al., 2014) ex-
known links to aging and/or age-related disease tends lifespan in C. elegans or D. melanogaster, respectively. Other in-
terventions have been shown to negatively impact lifespan. The absence
Since our larger list of 1,128 common proteins (Supplementary of either normal Col1a1 (Vafaie et al., 2014) or normal Fn1 (Muro et al.,
Table 2) included known regulators of aging, we were curious if these 2003) in mice generates animals with shortened lifespans. Mutants with
32 most common proteins (Table 2) had established links to aging and/ a targeted mutation in Col1a1 display features of premature aging
or age-related disease. A comprehensive literature search revealed that (Vafaie et al., 2014) and mice lacking the EDA exon of Fn1 exhibit
every one of these proteins had such a connection (Table 3). The impaired wound healing (Muro et al., 2003). Fn1 was also later iden-
overexpression of human GDF15, for example, extends both lifespan tified as a gene whose disruption accelerates the demographic rate of
and healthspan in mice (Wang et al., 2014). A recent study in mice aging in mice (Pedro de Magalhaes et al., 2018). As a nice corollary to
demonstrated that Gdf15 is necessary for metformin to mediate its the previously mentioned life extension reports (Hugosson et al., 2014;
beneficial effects on body weight and energy balance. Moreover, met- Iwasa et al., 2010), worms harboring a loss of function mutation in the
formin elevates circulating levels of GDF15 in both mice and humans worm EGF receptor let-23 (Liu et al., 2011) and null mutants lacking
(Coll et al., 2019). The latter findings are highly significant because, in pleiotrophin (Hugosson et al., 2014) have shorter lifespans. RNAi
addition to effectively treating diabetes in humans as well as extending knockdown against tpi-1 (worm ortholog of TPI) in C. elegans (Ralser
lifespan and healthspan in mice, compelling clinical data suggests that et al., 2007) or PARK7 fly orthologs (DJ-1α and DJ-1β) in D. melano-
patients taking metformin enjoy reduced mortality and a lower in- gaster (Lavara-Culebras and Paricio, 2007) additionally reduces long-
cidence of various age-related diseases (Barzilai et al., 2016). Very re- evity. In total, we were able to find known evidence that 10 of these 32
cent work has also found that the plasma proteins levels of GDF15, proteins impact lifespan in normal, non-diseased animals (Table 3).
CTSS, and THBS2 and are all significantly associated with mobility While we were not able to identify a known link to lifespan reg-
disability in the elderly (Osawa et al., 2020). These data as well as our ulation in non-diseased animals in the other proteins, we were able to
finding that GDF15 was reported to significantly change with age by find associations with longevity, mortality, and/or age-related disease
five different studies in plasma (Table 2) suggests that GDF15 is both a (Table 3). In a multi-species screen to discover proteins associated with
high-quality aging biomarker and a viable therapeutic target for im- higher maximal lifespans in mammals, CAPNS1 was found to exhibit a
proving human healthspan. longevity-specific selection pattern (Li and de Magalhaes, 2013).
5
Table 3
Reported roles relevant to aging and age-related disease for the 32 most common proteins identified to significantly change with age. FGA and FGG are included in
the same row as they both combine (along with FGB) to form the glycoprotein complex fibrinogen. Proteins reported to affect lifespan in non-diseased animals are
highlighted in bold.
Protein Reported Roles Relevant to Aging and Age-related Disease
ALB • Low albumin levels in hospitalized patients are associated with increased mortality (Akirov et al., 2017)
• InIn the
older adults, low serum albumin levels as well as sarcopenia both synergistically increase the risk of incident disability (Uemura et al., 2019)
ANXA1 • reducedearly stages, expression of ANXA1 is elevated in the brains of patients and mice with Alzheimer’s disease. Treatment with human recombinant ANXA1
the levels of amyloid-β and promoted the phagocytic clearance of amyloid-β by microglia (Ries et al., 2016)
• Human recombinant ANXA1 rescues amyloid-β-induced disruption of the blood-brain barrier in mice (Park et al., 2017)
ANXA2 • Expression level of ANXA2 is significantly associated with tumor invasion and lymph node metastasis. In patients with malignant tumors, overexpression of
ANXA2 is also correlated with poor prognosis with regards to overall survival and disease-free survival (Liu et al., 2015b)
• Inworse
response to sepsis, Anxa2−/−
mice exhibit an elevated level of pro-inflammatory cytokines, increased neutrophil infiltration, decreased bacterial clearance, and
survival. Reactive oxygen species and IL-17A levels are both intensified in mice lacking Anxa2 (He et al., 2016)
ATP5F1B • Treatment with α-ketoglutarate extends lifespan in C. elegans and this life extension requires the protein ATP synthase subunit beta. Direct inhibition of atp-2
(worm ortholog of ATP5F1B) via RNAi knockdown also prolongs longevity in C. elegans (Chin et al., 2014)
• atp5if1a is liver biomarker of hepatic damage in zebrafish (Ayobahan et al., 2020)
C3 • Inactivation
a mouse model of Alzheimer’s disease, animals genetically lacking C3 show an increased amyloid plaque burden, a substantial loss of neurons, and the
of a more inflammatory, alternative microglial phenotype (Maier et al., 2008)
• Inhibition of C3 in Alzheimer’s mice enhances neurodegeneration and plaque formation (Wyss-Coray et al., 2002)
C4A • Plasma levels of C4A are elevated in patients with neovascular age-related macular degeneration (Lechner et al., 2016)
• Increased copy number of C4A is associated with late-stage age-related macular degeneration (Grassmann et al., 2016)
• Copy levels of C4A are higher in patients with Alzheimer’s disease (Zorzetto et al., 2017)
CAPNS1 • Inlongevity-specific
a multi-species analysis to identify proteins associated with higher maximal lifespans in mammals, CAPNS1 was identified as a protein that exhibits a
selection pattern (Li and de Magalhaes, 2013)
• Deletion of Capns1 in mouse endothelial cells attenuates diabetic cardiomyopathy (Teng et al., 2019)
• Mice lacking cardiac Capns1 have hearts that are less resistant to hemodynamic stress (Taneike et al., 2011)
COL18A1 • Mice lacking Col18a1 undergo age-related degeneration of the retinal pigment epithelium and display signs of perturbed proteostasis (Kivinen et al., 2016)
• Human genetic variant of COL18A1 is associated with blood triglyceride levels (Peloso et al., 2014)
• Mice deficient in Col18a1 exhibit mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Human patients with a loss of function mutation in
COL18A1 also present with fasting hypertriglyceridemia (Bishop et al., 2010)
COL1A1 • Col1a1 r/r
mutant mice exhibit a shortened lifespan and features of premature aging, including hypertension, reduced bone mineral density, weight loss, and an
outward curvature of the spine (Vafaie et al., 2014)
• Mice lacking the first intron of Cola1 develop an increased age-dependent risk for aortic dissection and rupture (Rahkonen et al., 2004)
• Expression level of COL1A1 predicts survival and recurrence in patients with malignant astrocytoma (Sun et al., 2018b)
CTSS • Protein plasma levels of CTSS are significantly associated with the risk of losing mobility in older adults (Osawa et al., 2020)
• CTSS expression levels are associated with poor prognosis and lymph node metastasis in patients with papillary thyroid cancer (Tan et al., 2018)
• AGaingenetic variant of CTSS is correlated with fat body mass in humans (Pei et al., 2014)
EGFR • In C. ofelegans,
function mutation in let‐23 (worm EGF receptor) in C. elegans increases lifespan and enhances swimming vigor later in life (Iwasa et al., 2010)
• nematode lifespan EGF signaling upregulates the ubiquitin proteasome system. Introducing a loss of function mutation in the let-23 (worm EGF receptor) shortens
(Liu et al., 2011)
• EGFR is associated with human longevity (Park et al., 2009)
• EGFR is commonly expressed in human sarcomas (Borgatti et al., 2017)
• Smed-egfr-4, a planarian homolog of the EGFR family, is required for eye regeneration in Schmidtea mediterranea (Emili et al., 2019)
FGA, FGG • Concentration of fibrinogen is associated with patient mortality (Moeller et al., 2017)
• FGA levels are elevated in the cerebrospinal fluid of patients with Alzheimer’s disease and mild cognitive impairment (Lee et al., 2007)
• Plasma levels of fibrinogen are correlated with lung cancer risk (Grafetstatter et al., 2019)
• blood
Epigenetic aging is associated with the expression levels of fibrinogen’s three subunit-encoding genes (FGA, FGG, and FGB) in aorta intima-media and peripheral
(Ward-Caviness et al., 2018)
FN1 • Mutant mice lacking the EDA exon exhibited abnormal skin wound healing. Mice strains either lacking or harboring the constitutive inclusion of this exon had
shorter lifespans compared to controls (Muro et al., 2003)
• Fn1 was identified as a gene that accelerates the demographic rate of aging in mice (Pedro de Magalhaes et al., 2018)
GDF15 • improved
Transgenic mice expressing human GDF15 exhibit significantly increased lifespans, reduced body and adipose tissue weight, elevated energy expenditure, and
insulin sensitivity (Wang et al., 2014)
• InGDF15
mice, the beneficial effects of the anti-diabetic drug metformin on energy balance and body weight require Gdf15. Moreover, metformin elevates circulating
levels in mice and humans (Coll et al., 2019)
• Protein plasma levels of GDF15 are significantly associated with the risk of losing mobility in older adults (Osawa et al., 2020)
GOT1 • The microRNA miR-9-5p inhibits the proliferation and invasion of pancreatic cancer cells via the inhibition of GOT1 mRNA (Wang et al., 2019)
• Compared to ad libitum-fed mice, both caloric restriction and treatment with metformin decrease the serum levels of Got1 (Song et al., 2015)
GSTP1 • Transgenic nematodes overexpressing gst-10 (worm ortholog of GSTP1) live longer and are more resistant to oxidative stress, heat shock, and ultraviolet
irradiation (Ayyadevara et al., 2005)
• GSTP1 is frequently hypermethylated and underexpressed in multiple human cancers (Esteller et al., 1998; Martignano et al., 2016)
• Gstp1 expression is substantially reduced in short-lived mice lacking Siglec12 (Schwarz et al., 2015)
HGF • Overexpression of Hgf in the nervous system prolongs lifespan as well as attenuates motor neuron death and axonal degeneration in a mouse model of
amyotrophic lateral sclerosis (Sun et al., 2002)
• HGF attenuates inflammation and disease severity in a rat model of pulmonary artery hypertension (Pang et al., 2018)
• HGF derived from cancer-associated fibroblasts promotes the proliferation, migration, and invasion of gastric cancer (Ding et al., 2018)
• Gene expression levels of HGF are a biomarker for diabetic kidney disease (Tang et al., 2020)
HP • AExonic
genetic variant of this gene was reported to be associated with human parental lifespan (Melzer et al., 2019)
• Overexpression
deletion in HP correlates with reduced levels of LDL and total cholesterol (Boettger et al., 2016)
HNRNPDL • leukemia cells. Itofadditionally
HNRNPDL induces leukemia in vivo and, conversely, silencing HNRNPDL inhibits the colony-forming cell production of chronic myeloid
attenuates BCR-ABL-induced leukemia (Ji et al., 2019)
• Unlike control cells, injecting NIH-3T3 cells overexpressing HNRNPDL into nude mice generates tumors (Zhang et al., 2018)
LAMC1 • LAMC1 expression levels are elevated in glioma and predict a poor prognosis (Liu et al., 2019)
• ALAMC1
single nucleotide polymorphism near LAMCA1 associates with colorectal cancer (Whiffin et al., 2014)
LRP1
• expression is enriched in hepatocellular carcinoma samples and correlates with both poor overall survival and disease-free survival (Zhang et al., 2017)
(continued on next page)
6
Table 3 (continued)
Protein Reported Roles Relevant to Aging and Age-related Disease
• In(Brankatschk
Drosophilamelanogaster, glial-specific RNAi knockdown against both LRP1 and LRP2 extends lifespan, slows larval growth, and delays pupariation
et al., 2014)
• Mice lacking Lrp1 specifically in macrophages develop more atherosclerosis (Overton et al., 2007)
MMP12 • The deletion of Mmp12 in mice blocks arterial stiffening and decreases elastin degradation (Liu et al., 2015a). Mmp12-null mice also exhibit a decrease in age-
dependent arterial stiffening (Brankovic et al., 2019)
• Mmp12 is a robust senescence-associated secretory phenotype factor that consistently increases with age across diverse tissues in mice (Hudgins et al., 2018)
PARK7 • Mutations in PARK7 cause an autosomal recessive version of early-onset Parkinson’s disease (Bonifati et al., 2003)
• Mice lacking Park7 have a lower body mass, increased energy expenditure, and enhanced insulin sensitivity compared to controls. These mice are additionally
resistant to obesity and insulin resistance when fed a high-fat diet (Wu et al., 2017)
• and
Genetic impairment of or RNAi knockdown against PARK7 orthologs (DJ-1α and DJ-1β) in fruit flies reduces lifespan, increases susceptibility to oxidative stress,
induces motor impairments (Lavara-Culebras and Paricio, 2007)
• Flies lacking PARK7 orthologs (DJ-1α and DJ-1β) exhibit male sterility, a shorter lifespan, and a reduced climbing ability (Hao et al., 2010)
PLAUR • PLAUR expression levels are commonly elevated in different cancer types and are associated with a poor prognosis (Su et al., 2016)
• PLAUR polymorphisms are correlated with lung function decline (Barton et al., 2009)
PTN • Overexpression of the Drosophila pleiotrophin homologs miple1 or miple2 extends fly lifespan. Conversely, null mutants lacking these proteins exhibit shorter
lifespans (Hugosson et al., 2014)
• Chronic myelogenous leukemia stem cells upregulate the expression of PTN and this protein is required for pathogenesis in a mouse model of bone marrow cancer
(Himburg et al., 2019)
TF • Compared to healthy controls or patients with a benign ovarian tumor, TF blood levels are downregulated in patients with ovarian cancer (Swiatly et al., 2018)
• TFCompared
is underexpressed in stomach cancer tissue (Ryu et al., 2003)
TMPO • improved myogenesis −/−
to Lmna mice, mice also lacking Tmpo exhibited longer lifespans, increased body mass, enhanced proliferation of multipotent satellite cells, and
(Cohen et al., 2013)
• Association of TMPO with telomeres is impaired in Hutchinson-Gilford progeria syndrome (Chojnowski et al., 2015)
TNFRSF1A • TNFRSF1A plasma levels associate with a greater risk of progression from normal cognition to mild cognitive impairment. A higher concentration of TNFRSF1A
also predicts a steeper rate of cognitive decline on follow-up (Gross et al., 2019)
• In(Vasunilashorn
older community-dwelling adults (aged 65 years or older), individuals with higher TNFRSF1A serum levels were less likely to be able to walk 400 meters
et al., 2013)
• Two single-nucleotide polymorphisms in TNFRSF1A associate with coronary artery disease in older humans. In addition, aged mice lacking Tnfrsf1a develop less
atherosclerosis (Zhang et al., 2010)
TNFRSF1B • Gene knockdown against tnfrsf1b disrupts vascular homeostasis and induces the apoptosis of endothelial cells in zebrafish (Espin et al., 2013)
• Genetic variant of TNFRSF1B associated with hearing impairment in the elderly (Uchida et al., 2014)
• Loss of Tnfrsf1b exacerbates the severity and chronicity of experimentally-induced arthritis under inflammatory conditions in mice (Tseng et al., 2019)
TPI • RNAi inhibition of tpi-1 (worm ortholog of TPI) shortens lifespan in C. elegans (Ralser et al., 2007)
• TPI is more thermolabile in skin fibroblasts from progeria patients compared to normal fibroblasts (Tollefsbol et al., 1982)
VEGFA • Genetic variants of VEGFA are associated with human longevity (Del Bo et al., 2008)
• Inretinal
mice, increased expression of Vegfa induces multiple different age-related ocular pathologies, including cataracts and age-related macular degeneration-like
disease (Marneros, 2016)
• Transplantation of human mesenchymal stem cells engineered to secrete VEGF into a rat model of amyotrophic lateral sclerosis prolongs survival and slows down
the loss of motor function (Krakora et al., 2013)
COL3A1 was also identified (Li and de Magalhaes, 2013), which was assessed the top ten pathways that were overrepresented in KEGG
reported to change with age in three different proteomics aging studies (Fig. 1A), WikiPathways (Fig. 1B), Reactome (Fig. 1C), and GO BP
(Supplementary Table 2). Mmp12 is a robust senescence-associated (Fig. 1D). A recurrent, prevalent theme of immune activation was ap-
secretory phenotype factor whose gene expression increases with age parent in our results. Exemplar of this, the top enriched process in
across multiple different tissues in mice (Hudgins et al., 2018). The WikiPathways (Fig. 1B), Reactome (Fig. 1C), and GO BP (Fig. 1D) was
expression of MMP12 in plasma also increases with age in humans “human complement system”, “neutrophil degranulation”, and “gran-
(Lehallier et al., 2019). Since senescence is a hallmark of aging (Lopez- ulocyte activation”, respectively. In the KEGG database (Fig. 1A), the
Otin et al., 2013) and removing senescent cells is an established method second most enriched process was “complement and coagulation cas-
for enhancing lifespan and healthspan in mice (Gorgoulis et al., 2019), cades”. Other relevant results included “cytokine-cytokine receptor
this is a noteworthy connection. Either genetically removing or in- interaction” (Fig. 1A), “salmonella infection” (Fig. 1A), “complement
hibiting C3 in a mouse model of Alzheimer’s disease exacerbates neu- and coagulation cascades” (Fig. 1B), “cytokine signaling in the immune
rodegeneration (Maier et al., 2008; Wyss-Coray et al., 2002) and mice system” (Fig. 1C), and “leukocyte migration” (Fig. 1D). Several results
lacking Col18a1 develop age-related retinal degeneration (Kivinen relevant to the extracellular matrix were also identified. These include
et al., 2016). Compared to short-lived mice only lacking Lmna, mice “focal adhesion” (Fig. 1A), “focal adhesion” (Fig. 1B), “focal adhesion-
additionally lacking Tmpo benefit from longer lifespans, increased body PI3K-Akt-mTOR-signaling pathway” (Fig. 1B), “extracellular matrix
mass, greater proliferation of multipotent satellite cells, and improved organization” (Fig. 1C), and “extracellular structure organization”
myogenesis (Cohen et al., 2013). This is interesting as mutations in (Fig. 1D). “Focal adhesion” was the topmost result in the KEGG data-
LMNA cause the well-known progeria disorder Hutchinson-Gilford base (Fig. 1A) and the second most enriched result in the WikiPathways
Progeria Syndrome (Gonzalo et al., 2017). The remaining highlights for database (Fig. 1B). A few results were also pertinent to the regulation of
each protein are listed in Table 3. RNA, namely “mRNA processing” (Fig. 1B), “mRNA splicing – major
pathway” (Fig. 1C), and “posttranscriptional regulation of gene ex-
pression” (Fig. 1D). The canonical aging pathways insulin-IGF1 and
3.6. Enrichment analysis of common proteins identifies key processes that mTOR (Singh et al., 2019) were both implicated by the two results
change with age entitled “focal adhesion-PI3K-Akt-mTOR-signaling pathway” (Fig. 1B)
and “regulation of insulin-like growth factor (IGF) transport and uptake
We next performed a bioinformatics enrichment analysis on our by insulin-like growth factor binding proteins (IGFBPs)” (Fig. 1C). The
commonly identified proteins to determine what processes are im- following processes pertinent to hemostasis and blood flow were also
plicated by them. For the list of 1,128 common proteins that were identified: “complement and coagulation cascades” (Fig. 1A),
identified in two or more different studies (Supplementary Table 2), we
7
Fig. 1. Overrepresentation analysis results are shown for KEGG (A), WikiPathways (B), Reactome (C), and Gene Ontology Biological Process (GO BP) (D, E) looking
for significant overrepresentation (FDR < 0.05) among age-associated proteins identified in at least 2 studies (A–D) or at least 5 studies (E). The significance of
enrichment for the top weighted set cover terms is shown. The full names of the abbreviated processes with an ellipsis are “Focal Adhesion-PI3K-Akt-mTOR-signaling
pathway” (B), “Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)” (C), “generation of
precursor metabolites and energy” (D), “posttranscriptional regulation of gene expression” (D), and “negative regulation of response to external stimulus” (E). Results
are presented as -log10(FDR).
“complement and coagulation cascades” (Fig. 1B), “hemostasis” common proteins (Fig. 3A) as well as our most common proteins
(Fig. 1C), and “angiogenesis” (Fig. 1D). (Fig. 3B) to determine what drugs are enriched based on the protein
We also analyzed which GO terms were enriched in our 32 most targets provided. For the 1,128 proteins identified to change with age in
commonly identified proteins (Table 2). An overrepresentation analysis two or more different analyses (Supplementary Table 2), the top drug
showed that processes relevant to immune activation, extracellular enrichment results were “carbohydrates”, “cardiovascular system”,
matrix organization, and blood circulation were also overrepresented “trypsin”, “netilmicin”, “proteolytic enzymes”, “skeleton”, “im-
among the 32 most common proteins (Fig. 1E). Since this analysis was munoglobulins”, “tobramycin”, “amino acid”, and “l-lysine” (Fig. 3A).
limited by the small number of proteins involved, we used a network Three of these – namely the antibiotic netilmicin, immunoglobulins,
topology-based enrichment analysis to add the top 50 neighbors to and the antibiotic tobramycin – are directly linked to the immune
these 32 most common proteins using the BioGRID protein-protein in- system. It is interesting that the second most enriched result was
teraction network. The subsequent GO term enrichment analysis (32 “cardiovascular system”, as heart disease is the leading cause of death
most common proteins plus 50 network neighbors) identified the top 20 in the elderly (Ferrucci et al., 2008). Drug enrichment results in pro-
enriched GO terms (Fig. 2A) and quantified the significance of enrich- teins identified in five more different analyses (Table 2) were as follows:
ment for each one (Fig. 2B). Like we had seen in our analysis of all “human serum albumin”, “antithrombotic agents”, “serum albumin”,
1,128 common proteins (Fig. 1A–D), processes relevant to immune “collagenase”, “heparins or heparinoids for topical use”, and trypsin”
signaling (“cellular response to cytokine stimulus”, “response to cyto- (Fig. 3B). Since senescent cells impact blood clotting in vivo (Wiley
kine”), and the extracellular matrix (“extracellular structure organiza- et al., 2019) and cellular senescence levels increase with age (Tuttle
tion”, “extracellular matrix organization”) were again present (Fig. 2). et al., 2019), the “antithrombotic agents” and “heparins or heparinoids
Themes of cellular excretion and stress resistance were also apparent for topical use” results may reflect protein changes induced in part by
(Fig. 2). The results relevant to cellular excretion (i.e., “platelet de- senescent cells.
granulation”, “exocytosis”, “secretion by cell”, “secretion”) may be due Finally, we leveraged the GLAD4U Disease Enrichment analysis to
to every one of these proteins being reported at least once in plasma identify disease terms that might be enriched among proteins identified
(Table 2). Others were additionally reported in the following biofluids: in at least two (Fig. 3C) or five (Fig. 3D) studies. Among age-associated
serum, saliva, urine, or cerebrospinal fluid (Table 2). proteins that were identified in two or more studies, the top enriched
A GLAD4U Drug Enrichment analysis was then performed on all disease terms were “adhesion,” “inflammation,” “cardiovascular
8
Fig. 2. Network topology enrichment analysis was used to expand the network of our 32 most commonly identified aging proteins using protein-protein interactions
and taking the top 50 neighbors into account. The entire network was then tested for overrepresented GO terms and visualized as a dendrogram with enriched terms
in red and ancestors of enriched terms in beige (A). The top 20 enriched results – presented as -log10(FDR) – are also shown graphically (B).
diseases,” “drug interaction with drug,” “pregnancy complications,”, was the most commonly represented tissue in our systematic review
“fibrosis”, “pathologic process”, “stress”, “neoplastic process”, and (Table 1), we compiled a list of 23 proteins that were reported to sig-
“joint diseases” (Fig. 3C). When focusing in on just the age-associated nificantly change with age in plasma by four or more different studies
proteins identified in five or more studies, a different set of disease (Table 4).
terms was identified. These were “urination disorders,” “neoplasm in- To partially validate this dataset, we utilized a newly constructed,
vasiveness,” “neovascularization, pathologic,” “coronary artery dis- online proteomics and aging resource developed by Lehallier et al
ease,” “pleural effusion”, “hematologic diseases”, “skin and connective (Lehallier et al., 2019). This resource allows users to input a protein and
tissue diseases”, “liver cirrhosis”, and “seborrhea NOS” (Fig. 3D). These observe how it changes with age in their dataset of plasma proteomes
results further link inflammation and aging. Moreover, they highlight derived from over 4,000 human adult patients. Utilization of this online
multiple different age-related diseases, including cancer, arthritis, and interface enabled us to visualize the expression trend with age as well as
heart disease. determine the significance for the proteins in our proposed panel
(Table 4). We found that all of the identified proteins had a p-value <
0.05. With the exception of HGF, which had a q-value of 0.063241581,
3.7. Recommendation of a plasma protein panel to be utilized for human all of the proteins also had a q-value < 0.05. The four proteins that had
aging biomarking the most significant q-value changes with age were GDF15 (p =
2.33e−252, q = 1.71e−249), PTN (p = 6.12e−183, q =
An ideal proteomic biomarker of aging would be easily measurable, 2.24e−180), MMP12 (p = 2.16e−94, q = 2.53e−92), and NPPB (p =
involve a minimal set of proteins, and be able to reflect the acceleration 3.48e−87, q = 3.51e−85). The expression changes over time for these
or deceleration of aging. Given that blood is a highly appealing biofluid four proteins are visualized in Fig. 4. The graphs for the other proteins
for clinical biomarking (Johnson and Stolzing, 2019) and that plasma
9
Fig. 3. GLAD4U Drug Enrichment analyses were performed for all 1,128 proteins identified in at least two studies (A) as well as for all 32 proteins identified in at
least five studies (B). GLAD4U Disease Enrichment analyses were also performed for all 1,128 proteins identified in at least two studies (C) as well as for all 32
proteins identified in at least five studies (D). For each analysis, the top weighted set cover terms are shown. Results are presented as -log10(FDR).
Table 4
Proposed plasma protein panel to use as a proteomic aging clock. A total of 23 proteins are listed alphabetically (FGA, FGB, and FGG are counted as three separate
proteins but are listed as a single entry), each of which was reported to significantly change with age in plasma by four or more different studies. For each protein, the
UniProt ID as well as the number of times the protein was reported to significantly change with age in plasma is provided. The quantified p-value, the quantified q-
value, and the expression trend in a large proteomics plasma dataset derived from 4,263 patients aged 18–95 years are also listed.
Protein UniProt ID # of Times Reported in Plasma p-value, q-value Expression Trend
ADAMTS5 Q9UNA0 4 1.42e−66, 7.69e−65 Increase

ADM P35318 4 0.01243370, 0.02881821 Increase
CCDC80 Q76M96 4 6.93e−36, 1.93e−34 Increase
CHI3L1 P36222 4 1.7e−35, 4.68e−34 Increase
CXCL10 P02778 4 5.97e−49, 2.43e−47 Increase
F3 P13726 4 8.62e−09, 5.52e−08 Increase
FGA, FGB, FGG P02671, P02675, P02679 5, 4, 4 1.02e−11, 8.38e−11 Increase
FSTL3 O95633 4 1.89e−83, 1.63e−81 Increase
GDF15 Q99988 5 2.33e−252, 1.71e−249 Increase
HAVCR2 Q8TDQ0 4 9.36e−28, 1.93e−26 Increase
HGF P14210 4 0.03091811, 0.06324158 Increase
IGFBP6 P24592 4 2.14e−18, 2.69e−17 Increase
MMP12 P39900 5 2.16e−94, 2.53e−92 Increase
NPPB P16860 4 3.48e−87, 3.51e−85 Increase
PAPPA Q13219 4 2.24e−05, 9.29e−05 Increase
PLAUR Q03405 5 1.35e−17, 1.61e−16 Increase
PTN P21246 4 6.12e−183, 2.24e−180 Increase
TNFRSF11B O00300 4 4.21e−49, 1.74e−47 Increase
TNFRSF1A P19438 5 4.07e−22, 6.3e−21 Increase
TNFRSF1B P20333 5 2.32e−21, 3.47e−20 Increase
VEGFA P15692 4 5.38e−38, 1.68e−36 Increase
are shown in Fig. 5. Surprisingly, all of these proteins had a trend to- reported to change significantly with age in plasma in three or more
wards increased expression with age (Table 4, Figs. 4 and 5). different studies (Supplementary Table 5). We then analyzed these
While these data suggest that this panel of 23 proteins (Table 4) is proteins using the online proteomics and aging resource developed by
sufficient for aging biomarking, it is likely that the inclusion of addi- Lehallier et al (Lehallier et al., 2019). Two of these proteins – CST3 and
tional plasma proteins will make the aging clock more robust. With this EFEMP1 - were not available for measurement and we were therefore
in mind, we expanded our panel to include 85 proteins that were unable to include statistical information for them. With the exception of
10
Fig. 4. Expression trends with age are shown for GDF15 (A), PTN (B), MMP12 (C), and NPPB (D). Of the proteins included in our proposed proteomic aging clock
comprised of proteins reported to change with age in plasma in four or more different studies, these four showed the most significant age-dependent changes in a
large proteomic dataset derived from 4,263 human patients aged 18–95 years. A Loess regression line is shown for each protein. RFU = relative fluorescence unit.
FN1 (p = 0.546072212, q = 0.654883649), HGF (p = 0.030918106, q had a Pearson’s correlation of 0.66, a Spearman’s correlation of 0.69,
= 0.063241581), and KLK11 (p = 0.482173055, q = 0.597845319), and a mean delta age of 8.54 years (Fig. 6B). The results for the ex-
all other members of this panel had p- and q-values < 0.05. 10 of the panded protein panel were considerably more impressive. For the
measurable proteins showed a trend towards decreased expression learning set (Fig. 6C), we calculated a Pearson’s correlation of 0.9, a
(12.35 %) with age while the remainder showed a trend towards an Spearman’s correlation of 0.91, and a mean delta age of 4.88 years. For
increased expression (87.65 %) with age (Supplementary Table 5). A the test set, the Pearson’s correlation was 0.87, the Spearman’s corre-
larger list of 529 proteins reported to change with age in plasma by two lation was 0.88, and the mean delta age was 5.5 years (Fig. 6D). Thus,
more different studies is provided in Supplementary Table 6. both the shortened and extended versions of this proteomic aging clock
were capable of predicting human age. The extended protein panel is
3.8. Novel proteomic aging clock accurately predicts patient age in a large especially robust.
patient cohort
4. Discussion
Having proposed two versions of a novel proteomic aging clock, we
were curious if this clock could accurately predict patient age in a large In this systematic review, we have collated and analyzed multiple
patient cohort. We therefore directly assessed how capable this pro- different studies assessing proteomic changes in human aging. In ad-
teomic clock was in the INTERVAL cohort comprised of 3,301 human dition to identifying common proteins that change with human age, we
subjects aged 18–76 years (Sun et al., 2018a). In this large proteomic have discovered a plethora of proteins that are viable candidates for
dataset, all 23 proteins reported to change with age in plasma by four or anti-aging therapies as well aging biomarking. We have additionally
more different studies were measured. For the expanded panel com- utilized bioinformatics analyses to learn about what pathways and
prised of 85 proteins reported to change with age by three or more processes are implicated by our common aging proteins. Lastly, we
different studies, 83 proteins were measured. propose and fully validate a novel, robust proteomic aging clock.
We generated learning (n = 2,178) and test (n = 1,123) datasets With regards to aging clocks, we identified a large number of
and evaluated the prediction accuracy using Pearson and Spearman common proteins that were expressed in plasma and proposed two
correlations as well as by calculating the mean absolute delta age. For different protein panels that could be used to predict biological age. The
the 23 plasma proteins implicated by four or more different studies, the first, smaller panel includes proteins that were significantly changed
learning set had a Pearson’s correlation of 0.71, a Spearman’s correla- with age in four or more studies and the larger, extended panel includes
tion of 0.71, and a mean delta age of 8.17 years (Fig. 6A). The test set proteins that were reported to significantly change with age in three or
11
Fig. 5. Expression trends with age are shown for the remaining proteins (excluding GDF15, PTN, MMP12, and NPPB, which are shown in Fig. 4) in our proposed
proteomic aging clock comprised of proteins reported to change with age in plasma in four or more different studies. Plots are visualized for ADAMTS5 (A), ADM (B),
CCDC80 (C), CHI3L1 (D), CXCL10 (E), F3 (F), FGA.FGB.FGG (G), FSTL3 (H), HAVCR2 (I), HGF (J), IGFBP6 (K), PAPPA (L), PLAUR (M), TNFRSF11B (N), TNFRSF1A
(O), TNFRSF1B (P), and VEGFA (Q). These proteins were analyzed in a large, proteomic dataset derived from 4,263 human patients aged 18–95 years. A Loess
regression line is shown for each protein. RFU = relative fluorescence unit.
more studies. In addition to validating the individual proteins in these were reported to change with age in two or more different tissues and/
panels using publicly available proteomics data from over 4,000 pa- or cell types. This raises the intriguing possibility that a proteomic
tients (Lehallier et al., 2019), we demonstrate that these protein panels signature may exist that can predict biological age in multiple different
are bona fide aging clocks that can accurately predict patient age in a human tissues. A single protein clock that could be used to measure age
large patient cohort comprised of 3,301 subjects (Sun et al., 2018a). in a multitude of tissues would be remarkably useful and allow for easy
Within this dataset, there are curious outliers that have a predicted age standardization. We propose that a machine learning approach in a
which notably deviates from their chronological age. Similarly to what large, multi-tissue human dataset should be employed to explore this
has already been done using aging clocks comprised of methylated DNA possibility. If such a proteomic clock exists, it is also likely that the
(Horvath and Raj, 2018), it would be intriguing to determine if patients proteins that comprise the clock are highly relevant to aging. It is also
with a lower predicted age than their chronological age are typically probable that at least some of members of this theoretical clock would
healthier. Similarly, it would invaluable to determine if patients with a be viable therapeutic targets for healthspan-extending interventions.
higher predicted age than their chronological age are more likely to Since an epigenetic clock comprised of methylated DNA has already
harbor age-related disease. Since plasma protein profiles correspond been generated that can predict patient age in multiple different tissues
with different health states, lifestyle behaviors, and disease risk (Horvath, 2013), this goal of a pan-tissue protein clock is both feasible
(Williams et al., 2019), future studies should seek to optimize this and worth pursuing.
protein clock to enhance its ability to predict age and measure patient While diverse processes and pathways were implicated by our
health. Tailored aging clocks could potentially be created by mining our bioinformatics aging analyses, a prevalent and recurrent theme was the
list of 529 proteins that were reported to change with age in plasma by immune system. Other have shown that innate immune pathways are
two or more different studies. dysregulated with age in various vertebrate species (Benayoun et al.,
Looking at all of the proteins identified in our systematic review, we 2019), that chronic inflammation is strongly implicated in several age-
were surprised by the rather large number of common proteins that related diseases (Furman et al., 2019), and that unhealthy inflammation
were reported to significantly change with age in several different tis- contributes to the deleterious effects of aging (Lopez-Otin et al., 2013).
sues and cell types. Approximately 2/3 of all 1,128 common proteins The prominent theme of focal adhesions/extracellular matrix was an
12
Fig. 6. Using the INTERVAL cohort

comprised of 3,301 human subjects
aged 18–76 years, we assessed the
ability of our plasma proteomic aging
clock to predict human age. We tested
both the shortened version (made up of
proteins reported to change with age in
plasma by four or more different stu-
dies) as well as the elongated version
(made up of proteins reported to
change with age in plasma by three or
more different studies) of this aging
clock. Learning and test datasets were
generated for each version. A) For the
23-protein clock, the learning set (n =
2,178) had a Pearson’s correlation of
0.71, a Spearman’s correlation of 0.71,
and a mean delta age of 8.17 years. B)
The test set (n = 1,123) had a
Pearson’s correlation of 0.66, a
Spearman’s correlation of 0.69, and a
mean delta age of 8.54 years. C) For the
83-protein clock, the learning set (n =
2,178) had a Pearson’s correlation of
0.9, a Spearman’s correlation of 0.91,
and a mean delta age of 4.88 years. D)
For the test set (n = 1,123), the
Pearson’s correlation was 0.87, the
Spearman’s correlation was 0.88, and
the mean delta age was 5.5 years.
unexpected finding. Since cellular senescence is a hallmark of aging signaling pathway”, “response to toxic substance”, and “senescence and
(Lopez-Otin et al., 2013) and senescent cells are associated with ex- autophagy in cancer”. In our 32 most commonly identified proteins,
tracellular matrix alterations (Mavrogonatou et al., 2019), this theme relevant enriched GO terms included “response to stress” and “regula-
may reflect the increase in senescent cells that occurs with age in tion of response to stress”. Ergo, our findings suggest that repair /
human tissues (Tuttle et al., 2019). Senescent cells also secrete he- maintenance mechanisms are significantly changed over time and lend
mostasis-related factors (Wiley et al., 2019) and, relevantly, “hemos- credence to the theory that dysregulated repair mechanisms contribute
tasis” was the fourth most enriched result produced by our analysis in to growing dysfunction with age. They additionally corroborate the
Reactome. We additionally found that a large number of proteins in- evolutionary theories of aging, which predict that animals with greater
volved in lipid metabolism were commonly reported to change with longevity have evolved more robust repair mechanisms to help thwart
age. For example, fatty acid synthase (FASN) was reported four dif- aging (Johnson et al., 2019).
ferent times, fatty acid-binding protein, liver (FABP1) was reported We find it likely that interventions targeting a subset of our com-
three different times, and phospholipase A2, membrane associated monly identified aging proteins have the potential to mitigate aging and
(PLA2G2A) was reported two different times. The latter finding is improve health. One of the more promising candidates we identified is
especially interesting as knocking out the phospholipase A2 receptor in GDF15, which was reported to change with age in plasma by five dif-
progeria mice significantly improves healthspan (Griveau et al., 2018). ferent studies. Not only does the overexpression of GDF15 extend life-
More broadly, lipid metabolism and lipase enzymes have been im- span and healthspan in mice (Wang et al., 2014), but the beneficial
plicated in the regulation of both lifespan and healthspan (Johnson, effects on body weight and energy balance induced by the diabetic drug
2019). Another interesting finding was that a large number of collagen metformin require GDF15 (Coll et al., 2019). Moreover, exercise in-
proteins were reported to change significantly with age in two or more creases the levels of circulating GDF15 in humans (Kleinert et al., 2018)
different studies. Given this and that COL3A1 was previously identified and plasma protein levels of GDF15 are associated with the risk of
as a protein that exhibits a longevity-specific selection pattern (Li and mobility disability in the elderly (Osawa et al., 2020). These data all
de Magalhaes, 2013), the relationship between collagen and aging suggest that GDF15 is highly relevant to aging and that strategies which
should be explored more thoroughly. elevate levels of GDF15 may yield desirable benefits. Since plasma le-
Long-lived species have been reported to exhibit more efficient DNA vels of GDF15 increase with human age (Lehallier et al., 2019), it is
repair (Evdokimov et al., 2018; Tian et al., 2019) and superior pro- possible that more GDF15 is produced in response to aging stressors.
teome stability (Treaster et al., 2014). They also harbor unique genetic Another anti-aging candidate is the metabolite α-ketoglutarate. In C.
changes relevant to cancer resistance and development (Keane et al., elegans, Chin et al demonstrated that α-ketoglutarate extends lifespan
2015; Quesada et al., 2019). We were therefore curious if any of the and provided evidence that this life extension requires ATP synthase
processes and pathways implicated by our large set of common aging subunit beta (Chin et al., 2014). A mimetic of this metabolite, 2,4-
proteins were pertinent to repair or maintenance. Among the various pyridinedicarboxylic acid, similarly boosts longevity in worms (Mishur
databases analyzed, we identified the following phrases/terms: “he- et al., 2016). In fruit flies, dietary α-ketoglutarate prolongs life, en-
mostasis”, “negative regulation of proteolysis”, “regulation of apoptotic hances vertical climbing ability, and increases heat stress resistance (Su
13
et al., 2019). This same metabolite plays imperative roles in stem cell Research Foundation, Mountain View, California, United States) and
renewal and maintenance (Carey et al., 2015; TeSlaa et al., 2016), AAJ would like to thank Dr. Leili Rohani (University of Calgary,
which is interesting since stem cell exhaustion is a classic hallmark of Calgary, Canada) for helpful correspondence and support. AAJ and
aging (Lopez-Otin et al., 2013). It would be intriguing to know if α- MNS are additionally thankful to JL, ES, BS, YS, and JM.
ketoglutarate can yield desirable anti-aging benefits in vertebrate
model organisms. More broadly, we suggest that the more commonly Appendix A. Supplementary data
identified proteins in our systematic review represent a good source of
anti-aging drug candidates that should be explored more thoroughly. Supplementary material related to this article can be found, in the
While this study offers unique insights into aging, it does have online version, at doi:https://doi.org/10.1016/j.arr.2020.101070.
limitations. The most prominent limitation is that the systematic review
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Ageing Research Reviews 60 (2020) 101070

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Ageing Research Reviews

Systematic review and analysis of human proteomics aging studies unveils a T

ARTICLE INFO ABSTRACT

3. Results A number of these common proteins have prominent aging con-

Blood; plasma 4263 18-95 SOMAscan 1359 (Lehallier et al., 2019)

(continued on next page)

Protein Reported Roles Relevant to Aging and Age-related Disease

ADAMTS5 Q9UNA0 4 1.42e−66, 7.69e−65 Increase

Fig. 6. Using the INTERVAL cohort

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