Endocrinology, 2021, Vol. 162, No.

10, 1–12
https://doi.org/10.1210/endocr/bqab136
Mini-Review

Mini-Review

Role of Cellular Senescence in Type II Diabetes

Akilavalli Narasimhan,1,* Rafael R. Flores,1,* Paul D. Robbins,1 and
Laura J. Niedernhofer1

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1
Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and
Biophysics, University of Minnesota Medical School, 55455, USA
ORCiD numbers: 0000-0003-1068-7099 (P. D. Robbins); 0000-0002-5580-6381 (L. J. Niedernhofer).

*These authors contributed equally

Abbreviations: AGE, advanced glycation end product; AT, adipose tissue; BAT, brown adipose tissue; DDR, DNA damage
response; DR, diabetic retinopathy; ECM, extracellular matrix; ER, endoplasmic reticulum; IL, interleukin; IR, insulin
resistance; FFA, free fatty acid; NET, neutrophil extracellular trap; NF-κB, nuclear factor kappa B; ROS, reactive oxygen
species; SA-β-gal, senescence-associated beta-galactosidase; SAHF, senescence-associated heterochromatin foci;
SASP, senescence-associated secretory phenotype; SnC, senescent cell; T2D, type II diabetes; UPR, unfolded protein
response; VSMC, Vascular smooth muscle cell; WAT, white adipose tissue
Received: 15 April 2021; Editorial Decision: 28 June 2021; First Published Online: 7 August 2021; Corrected and Typeset:
25 August 2021.

Abstract
Cellular senescence is a cell fate that occurs in response to numerous types of stress and
can promote tissue repair or drive inflammation and disruption of tissue homeostasis
depending on the context. Aging and obesity lead to an increase in the senescent cell
burden in multiple organs. Senescent cells release a myriad of senescence-associated
secretory phenotype factors that directly mediate pancreatic β-cell dysfunction, adipose
tissue dysfunction, and insulin resistance in peripheral tissues, which promote the onset
of type II diabetes mellitus. In addition, hyperglycemia and metabolic changes seen in
diabetes promote cellular senescence. Diabetes-induced cellular senescence contributes
to various diabetic complications. Thus, type II diabetes is both a cause and consequence
of cellular senescence. This review summarizes recent studies on the link between aging,
obesity, and diabetes, focusing on the role of cellular senescence in disease processes.
Key Words: Diabetes, cellular senescence, aging, obesity, senotherapeutics, inflammation

Introduction
Type II diabetes (T2D) is a growing public health problem.
Older adults make up the largest segment of people with
T2D, and as the number of individuals over 65 is growing
rapidly, so is the incidence of T2D (1). One hundred and
eleven million cases of T2D were reported in the year 2019
among people over 65 years of age. In this age group, it
is estimated that 1 out of 5 people have T2D (2). Aging
and obesity are the predominant T2D risk factors and are
also associated with an increased burden of senescent cells
(SnCs). While cellular senescence is reported to contribute
to the pathogenesis of diabetes, the diabetic microenviron-
ment also seems to increase the burden of SnCs (3).
Cellular senescence is a state of indefinite cessation
of the cell cycle. Senescence can be triggered by mitotic
stress, DNA damage, telomere erosion, mitochondrial

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2 Endocrinology, 2021, Vol. 162, No. 10

dysfunction, oxidative stress, inflammation, mechanical
stress, and oncogenic activation (Fig. 1). Some, but not
all, SnCs develop a senescence-associated secretory pheno-
type (SASP), comprising a variety of factors that include
proinflammatory interleukins, chemokines, growth factors,
proteases, receptors, enzymes that modify the extracellular
matrix (ECM), stem cell/progenitor toxins, reactive me-
tabolites, bioactive lipids, microRNAs, and extracellular
vesicles. Evidence suggests that the role of SASP is to induce
the immune system to clear the damaged SnCs, since they
themselves are often resistant to apoptosis. However, with
in SnCs plays a positive role in tissue repair, likely through
the secreting the factors that remodel tissue locally and ac-
tivate the immune system to limit that remodeling (10). In
young healthy animals, senescence is induced transiently
upon tissue injury and is essential for the restoration of
tissue homeostasis (10-12).
Hallmarks of Cellular Senescence
Cell cycle arrest, mediated by upregulation of the cell
cycle inhibitors p16INK4a (p16), p15INK4b (p15), p19ARF,
and p21CIP (p21), is a universal characteristic of SnCs (Fig.

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age, immune system function wanes contributing to an in-
creased burden of SnCs in older organisms. Senescence is
a conserved tumor suppressor mechanism that prevents
replication of a damaged genome and mutagenesis (4). No
known physiologic stimuli can cause SnCs to re-enter the
cell cycle (5, 6). Thus, the cell cycle arrest in SnCs is con-
sidered irreversible. Expression of p16INK4a, a cell cycle in-
hibitor and tumor suppressor, increases exponentially with
chronologic age, suggesting that SnCs accumulate more
rapidly in old age (7), likely due to both an increased in-
duction and decreased immune clearance (8). Chronic sen-
escence is established to play a causative role in aging and
many age-related diseases (9). However, an acute increase
1). However, it is not a specific marker of senescence, be-
cause multiple cellular mechanisms can drive cell cycle
arrest. Upregulation of cell cycle inhibitors is also not a
pan-senescence marker since various cell cycle regulators
are engaged in different cell types and also in response to
difference inducers of senescence. SnCs do not respond to
mitogenic signaling, which distinguishes them from quies-
cent cells (13).
Most, if not all, SnCs show signs of DNA damage re-
gardless of the mechanism inducing senescence, including
increased γ-H2AX foci, 53BP1 foci, telomere-associated
foci (TAF), and de-condensation of pericentromeric satellite

Figure 1. Characteristics of senescent cells. SnCs have upregulation of the cell cycle inhibitors p16INK4a and p21CIP1. In addition, SnCs show telomere
shortening or damage (TAF), and epigenetic changes (SAHF). SnCs have decreased levels of nuclear Lamin B1 and increased lysosomal SA-β-gal
activity. Many SnCs have a SASP comprised of chemokines, inflammatory factors and interleukins, growth factors and regulators, extracellular ma-
trix components, soluble receptors, proteases and regulators, reactive metabolites, bioactive lipids, microRNAs, and extracellular vesicles. Early in
senescence, SnCs secrete HMBG1, a key DAMP (an endogenous molecule that activates the innate immune system), which amplifies the SASP. There
is no senescent-specific marker and not all SnCs express the same markers, especially in terms of the SASP. ROS, reactive oxygen species; SA-β-gal,
senescence-associated β-galactosidase; SAHF, senescence-associated heterochromatin foci; SASP, senescence-associated secretory phenotype; TAF,
telomere-associated foci. Figure created with BioRender.com.
Endocrinology, 2021, Vol. 162, No. 10
heterochromatin (senescence-associated heterochromatin
foci) (14) (Fig. 1). DNA damage is a direct inducer of sen-
escence through DNA damage response (DDR) signaling
mechanism (15). For example, double-strand breaks are
potent activators of the DDR initiate by identification of
a broken DNA end by the MRE11/RAD50/NBS1 complex
and recruitment of ataxia-telangiectasia mutated (ATM)
kinase to that site. ATM functions as a signal transducer,
activating hundreds of effector proteins through its kinase
activity to promote DNA repair. This includes phosphor-
ylation of the histone H2AX, leading to γ-H2AX foci at
sites of DNA repair (16). ATM also phosphorylates and
activates p53, which leads to the transcriptional activa-
tion of many genes that can mediate senescence if the DDR
signaling persists (17). γ-H2AX nuclear foci or phosphor-
ylated p53 are commonly used as markers of senescence,
although, again, they are not specific to SnCs.
As described above, SnCs secrete cytokines, chemokines,
and proteases, which are collectively referred to as the SASPs
(Fig. 1). SASP factors also are not specific to SnCs and can
play both positive and negative roles in several biological
processes such as wound healing and cancer progression
(10, 18). The upregulation of SASP factors is mediated by
the proinflammatory transcription factor nuclear factor
kappa B (NF-κB) (19). A major inducer of NF-κB activa-
tion is the DDR. GATA4 and C/EBPβ are other transcrip-
tion factors involved in the regulation of SASP genes (20,
21). However, these transcription factors play myriad roles
in cells and are not unique to SnCs.
Other characteristics of SnCs include increased protein
content, partly regulated through increased mTOR activity,
increased expression of senescent cell antiapoptotic proteins,
and increased activity of lysosomal senescence-associated
beta-galactosidase (SA-β-gal) (22). SnCs are metabolically
active with increased AMP:ATP and ADP:ATP ratios (23).
Multiple conditions, such as oxidative stress, mutations,
infections, and lack of chaperones, can cause endoplasmic
reticulum (ER) stress, leading to the accumulation and ag-
gregation of proteins. ER stress initiates the unfolded pro-
tein response (UPR), resulting in reduced protein synthesis,
enlarged ER, and export of misfolded proteins. SnCs have
an increased UPR, possibly in response to the increased
protein demand of SASP (24, 25).
A key morphologic feature of SnCs, at least in vitro, is
an enlarged and irregularly shaped cell body (26) (Fig. 1).
This is driven by cytoskeleton rearrangement, primarily
vimentin filaments (24). Another hallmark of SnCs is the
loss of lamin B1, a structural protein of the nuclear lamina.
The destabilization of the nuclear integrity caused by re-
duced lamin B1 results in other nuclear changes, such as
the loss of condensation of constitutive heterochromatin
and the appearance of cytoplasmic chromatin fragments
3
enriched in epigenetic marks associated with DNA damage
(27). The most consistent change in the plasma membrane
composition in SnCs is the upregulation of caveolin-1, an
essential component of cholesterol-enriched microdomains
called caveolae. Caveolin-1 contributes to the morphology
of SnCs (28).
SnCs have upregulation of many lysosomal proteins and
increased content, detected as increased SA-β-gal activity
(29) (Fig. 1). Increased lysosomal content could result from
the metabolic demands of SnCs and enhanced lysosomal
biogenesis. However, residual bodies, namely lipofuscins
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in SnCs, support the lack of lysosomal removal (30). SnCs
also have increased mitochondria content. The membrane
potential of SnC mitochondria is often decreased, leading
to the release of mitochondrial enzymes and increased re-
active oxygen species (ROS) production (31) (Fig. 1). The
major source of the extra-mitochondrial content is the ac-
cumulation of dysfunctional mitochondria due to reduced
mitophagy (32). This is, at least in part, a consequence of
reduced mitochondrial fission and increased fusion (33).
Senotherapeutics
Molecules that can specifically kill SnCs (senolytics)
or dampen their SASP and other senescence markers
(senomorphics) have been identified (34). Senolytics often
target pro-survival pathways upregulated in SnCs, which
include BCL-2-BCL-XL, p53-p21, and PI3K-AKT, resulting
apoptosis of the SnC. The first senolytic drugs identified
were the natural product fisetin (35), the combination of
dasatinib and quercetin (D + Q) (34), HSP90 inhibitors
(36), and Navitoclax (37). Additional natural products,
novel compounds, and re-purposed FDA approved drugs
with senolytic activity were identified more recently (38,
39). Drugs with senomorphic activity include the mTOR
inhibitor rapamycin, used clinically as an immunosuppres-
sant, and inhibitors of IKK-NF-kB and JAK-STAT (40). In
addition, metformin, a drug used to treat T2D, prevents
NF-κB activation (41), thereby reducing SASP and acting
as a senomorphic.
Senescence Drives Aging
Various markers of senescence, including SA-β-gal, p16,
TAFs, and activation of the DDR, are increased in tissues
of aged mammals, including rodents (42-44), baboons
(45, 46), and humans (47-49), suggesting a link between
SnCs and age-associated pathologies. Studies performed
using BubR1H/H mice, which age rapidly due to an insuf-
ficiency of a pivotal mitotic checkpoint protein, revealed
a causal link between SnCs and aging (50). Prematurely
aged tissues in this model, including skeletal muscle, eye,
4
and adipose tissue (AT), accumulate high-level of p16Ink4a-
positive SnCs, which contribute to the sarcopenia, cata-
racts, and lipodystrophy. The onset of these disease is
delayed in BubR1H/H mice when p16Ink4a-expressing cells
are ablated via drug-induced activation of transgenic
caspase-8, expression of which is driven by the p16 pro-
motor (referred to as the INK-ATTAC construct) (51).
Elimination of SnCs in aged wild-type INK-ATTAC mice
results in an extension in the median but not maximal
lifespan, suggesting that SnCs contribute to mortality in
mice. The Ercc1−/Δ mouse model of a human progeroid
syndrome (52) has reduced expression of the ERCC1-XPF
endonuclease, which is essential for multiple DNA repair
mechanisms. Ercc1−/Δ mice spontaneously develop senes-
cence in multiple organs, including AT, liver, and pancreas,
and interestingly a similar distribution of SnCs is seen
in aged wild-type mice (53-55). Removal of SnCs using
senolytic drugs blunts multiple aging features in Ercc1−/Δ
mice and aged wild-type mice, including renal dysfunction,
liver damage, pancreatic damage, and neurodegeneration,
while improving strength and endurance, and activity (9,
35, 56). Collectively, these studies demonstrate that SnCs
drive age-related morbidity and mortality (57).
Cellular Senescence in Pathogenesis of
Diabetes
The role of SnCs in diabetes is complex. SnCs play a part
in T2D pathophysiology through a direct effect on pancre-
atic β-cell function, participation in AT dysfunction, and
SASP-mediated tissue damage (58, 59). Metabolic changes
observed in diabetes, such as high circulating glucose and
altered lipid metabolism, can also stimulate SnC formation
(60). Thus, SnCs could be part of a pathogenic loop in dia-
betes, as both a cause and effect of metabolic changes and
tissue damage (58).
Pancreatic β-Cells
Defective insulin secretion in T2D is caused by β-cell dys-
function and reduced β-cell mass. β-cell dysfunction is
caused by chronic hyperglycemia and/or hyperlipidemia,
referred to as glucotoxicity and lipotoxicity, respectively
(61). Chronically high levels of free fatty acids (FFAs) and
glucose are toxic to β-cells, which can manifest in the form
of ER stress, the production of ROS, and/or mitochondrial
dysfunction (62, 63). To further complicate matters, β-cells
respond to FFA by producing and secreting inflammatory
cytokines (interleukin [IL]-1β, IL-6, IL-8) and chemokines
(CCL2, CXCL1) (64), of which IL-1β is a major player
and its secretion affects the activation of resident immune
cells (65). β-cells mediate their response to FFA through
Endocrinology, 2021, Vol. 162, No. 10
the toll-like receptor 4 (TLR4)-MyD88 pathway, which
leads to the activation of NF-κB (64, 66). Experiments with
isolated human islet cells or with mouse cell lines (MIN6,
INS-1) revealed that TLR4 is required for the secretion of
IL-1β following exposure to high FFA concentrations (66).
Knock-down of TLR4 or Myd88 expression, or blocking
the signaling pathway, attenuates production of IL-1β, and
insulin production is restored.
Numerous studies have documented the accumulation of
macrophages (MΦ) within islets of T2D patients and mouse
models of obesity and diabetes (66-69). Infiltration and po-
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larization of MΦ from an anti-inflammatory (M2) profile
towards a proinflammatory (M1) profile (CD11b+Ly-6C-
MΦ) are characteristic of islets in T2D (64). Several mouse
models of obesity, as well as mice placed on a high-fat diet
(HFD), display a similar increase in islet MΦ. The secretion
of chemokines like CCL2 and CXCL1 help to recruit cir-
culating monocytes that convert into CD11b+Ly-6C+ MΦ.
T cells are not increased in islets of mouse models of T2D,
however, increased B cells are detected (70). In fact, a small
percentage of T2D patients test positive for autoantibodies
to islet proteins (71, 72) (insulin, insulinoma-associated
protein-2, glutamic acid decarboxylase), which occurs most
frequently in older patients who have had diabetes for a
longer duration. Additionally, T2D patients can also have
auto-reactive T cells, which in some elderly patients can
occur in the absence of autoantibodies.
Glucose tolerance worsens with age in T2D, reflecting
a progressive reduction in the responsiveness of β-cells
to glucose stimulation and reduced sensitivity of periph-
eral tissues to insulin. Prior to the onset of hyperglycemia,
β-cells can compensate for increased metabolic demands
with increased insulin secretion. However, this compen-
sation becomes limited by the age-related decline in β-cell
proliferation seen in both rodents (73) and humans (74).
This lack of proliferation in response to increased insulin
demand may arise partially from the accumulation of sen-
escent β-cells (75).
Evidence for senescent β-cells includes diminished
β-cell proliferation and increased expression of senescence
markers are found in diet-induced T2D mice (76) and the
telomere length in β-cells from patients with T2D is signifi-
cantly shorter than in the control subjects (77). High-glucose
drives oxidative stress in β-cells, which may contribute to
telomerase dysfunction those cells (78). Haploinsufficiency
of Tert in mice shortens telomeres, including in β-cells.
This leads to fasting hyperglycemia, increased expression
of p16Ink4a in pancreatic islets, and impaired mitochon-
drial membrane hyperpolarization and Ca2+ mobilization
β-cells, which are crucial for insulin exocytosis (79).
The number of SA-β-gal+ cells is increased in islets iso-
lated from the pancreas of healthy older people compared
Endocrinology, 2021, Vol. 162, No. 10
to young, and this is increased further in islets from T2D
patients compared to nondiabetic, suggesting that β-cell
senescence might contribute to the pathogenesis of T2D
(80). In mice, SA-β-gal+ β-cells have decreased expres-
sion of β-cell identity genes (Ins1, Pdx1, Mafa, Neurod1)
with a concomitant increase in expression of markers
of senescence (p16 and p21), and SASP (Ccl2, Il1α, Il6,
Tnfα). Senescent β-cells have increased basal insulin se-
cretion (81) and are transcriptionally rewired, displaying
decreased expression of genes required for cellular de-
polarization, incretin signaling, and production of insulin
granules (82), all necessary for insulin secretion.
Senescent β-cells have also occurred in the pancreas
of patients with type 1 autoimmune diabetes (T1D) com-
pared with nondiabetic people and individuals who are
autoantibody positive prior to onset of T1D (83). This
suggests a correlation between disease progression and the
level of senescent β-cells. In the nonobese diabetic mouse,
an animal model of T1D, SnCs and SASP increase with
time in pancreatic islets (83). Senolytics reduce senescence
markers and the incidence of diabetes in these mice (83).
In mice placed on an HFD, the onset of insulin resistance
(IR) is associated with senescent β-islet cells and senolytics
can restore glucose metabolism (84). p16INK4a expression
increases in human and mouse β-cells with age, and this
contributes to their reduction in regenerative capacity
(79, 85, 86). Clearance of p16Ink4a+ cells in mice, using
the INK-ATTAC construct, improves glucose metabolism
and insulin secretion, while decreasing the expression of
proinflammatory SASP factors in islets (80). The senolytic
ABT263 (Navitoclax), reverses hyperglycemia and restores
the normal β-cell gene expression profile mice with induced
insulin resistance caused by the insulin receptor antagonist
S961 (80). The BCL-2 pathway, 1 of several anti-apoptotic
pathways, is upregulated in SA-β‐gal+ β‐cells, consistent
with ABT263 killing SA-β‐gal+ islet cells in vitro (80).
Adipose Tissue Senescence and Inflammation
AT is the largest and most active endocrine organ for
regulating energy balance, glucose and lipid homeostasis,
and immunity in response to the fluctuation in nutritional
status, environment, lifestyle, and aging (87). White adipose
tissue (WAT) stores surplus energy in the form of triglycer-
ides that are hydrolyzed into FFA and glycerol for energy
supply during nutrient deprivation. Brown AT (BAT) or
beige adipocytes convert chemical energy, mainly FFA, into
heat via the mitochondrial uncoupling reaction to maintain
core body temperature and energy balance. The amount
and function of AT are closely associated with age, calorie
intake, physical activity, and health status. An increase in
visceral WAT (vWAT), but not subcutaneous WAT (sWAT)
5
with obesity is causatively associated with T2D and cardio-
vascular diseases. vWAT is more prone to senescence com-
pared to sWAT (88). Senescent AT impairs lipid handling,
while promoting IR, defective adaptive thermogenesis,
aberrant adipocytokine production, and interferes with
normal physiological functions of other metabolic organs
via SASP.
BubR1H/H mice display dramatic loss of sWAT and
AT senescence (89). Clearance of these p16Ink4a+ cells in
BubR1H/H; INK-ATTAC mice reverses AT senescence,
thereby, preventing aging-related lipodystrophy (9).
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AT from obese individuals exhibits increased oxidative
stress and telomere shortening, which induce senescence.
Intracellular ROS activates p38 mitogen-activated protein
kinases, which in turn induces p53-p21–dependent senes-
cence (87). IR is one of the consequences of AT senescence
when p53 is activated. Transgenic mice with overexpression
of p53 have increased senescence and IR, whereas p53 in-
activation results in the opposite effects in diabetic mice
(59, 90).
Metabolic stress induced by high calorie intake in-
duces an inflammatory microenvironment, in particular in
AT. This affects not only resident immune cells, but also
infiltrating immune cells, which heighten inflammation
and contribute to IR through secretion of inflammatory
cytokines (82, 91-93). Excessive nutrient intake activates
adipocytes to internalize and accumulate FFA through
a CD36-driven mechanism regulated by PPARγ (94-
96). Adipocytes respond to the accumulation of lipids by
enlarging and proliferating and initiating an inflammatory
response through an HIF1α-NF-kB–driven mechanism (97-
99). Similar to adipocytes, adipose resident MΦ also accu-
mulate FFA through CD36. These MΦ further contribute to
the inflammatory response by secreting TNF-α, IL-6, Il-1β,
MCP-1, CX3CL1, and IL-8 (94, 95, 100). vWAT of wild-
type and db/db mice on a HFD exhibit elevated markers of
senescence (SA-β-gal, p16Ink4a) (101), a diminished capacity
to clear glucose upon challenge, and IR. Senolytics signifi-
cantly improve glucose tolerance and insulin sensitivity
(101). Exercise has a similar effect as senolytics in these
diabetic mice (102).
There are numerous interactions between the immune
system and AT during obesity that contribute to IR (Table
1). This inflammatory response, and the subsequent hyper-
glycemia, enhances the formation of SnCs, which can ex-
acerbate IR (83, 84). The number of senescent adipocytes
increases the number of MΦ positive for the cyclic ADP
ribose hydrolase CD38 (103). CD38 expression increases
along with inflammatory and senescence markers in the
AT of old mice, in addition to CD68, a marker of active
MΦ (103). Increased CD38 drives depletion of the critical
metabolite NAD+ (104). The increase in IR is paralleled
6 Endocrinology, 2021, Vol. 162, No. 10

Table 1. A short list of the interactions occurring between immune cells and inflamed adipose tissue

Immune cell subsets Impact on adipose tissue

T cells Peripheral CD8+ T cells infiltrate inflamed AT (92, 93, 100, 136)
Infiltrating T cells adopt a Th1 (interferon secreting) or a Th17 (IL-17-secreting) profile (93, 137-139)
Decreased antigen specificities recognized by infiltrating CD8+ T cells (100)
Resident CD4+ regulatory T cells maintain AT homeostasis through PPARγ. However, during obesity, the frequency
of resident CD4+ regulatory T cells decreases (136, 140-143)
Macrophage Infiltration into AT mediated by MCP-1 chemokine secreted by resident T cells (97, 136)
Excessive nutrients induce activation of MΦ driven through HIF1α, NF-κB, and IL-1β (94, 95, 136, 144)
DC Infiltration into AT mediated by CX3CL1 chemokine secreted by resident T cells (97, 145)
In lean mice, DCs exhibit a CD11c+CD103+ phenotype that induces CD4+Foxp3+ Tregs to maintain AT homeostasis.
In obese or db/db knockout mice, DC exhibit a CD11c+F4/80lo phenotype and induce Th17 cells (145, 146)

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Other innate cells In lean conditions, innate lymphoid cells type-2 induce anti-inflammatory responses and attenuate insulin resistance,
but this is lost during obesity (147-149)

Abbreviations: AT, adipose tissue; DC, dendritic cell; IL, interleukin; NF-κB, nuclear factor kappa B.

by an increase in senescent T cells both in humans and
mice (105). Older T2D patients have elevated levels of
CD8+CD57+CD28– T cells, which exhibit markers of sen-
escence. Levels of senescent CD8+ T cells are increased in
pre-diabetics compared to nondiabetic controls and may be
predictive of the development of hyperglycemia (105, 106).
Senescent T cells in mice, defined as CD8+CD44+PD-1+,
are elevated in old wild-type mice placed on a HFD for
2 months, which leads to IR, inflamed AT, and increased
SnCs in AT and liver (105). Notably, driving senescence in
the immune system alone, is sufficient to drive increased
expression of senescence markers in pancreatic tissue and
organ damage, as determined by serum amylase levels (107).
Peripheral Tissues
Fat is redistributed outside fat depots with aging, accumu-
lating in muscle, liver, bone marrow, and other ectopic sites.
Insulin-resistant hypertrophic adipocytes have augmented
lipolytic activity and diminished ability to take up FFA, re-
sulting in a redirection of lipids toward nonadipose tissues
(ectopic fat deposition) (108). If fatty acid β-oxidation in the
mitochondria cannot keep up with the increased supply of
FFA to nonadipose tissues accumulation of lipid intermedi-
ates like diacylglycerol and ceramides occurs. These lipid
intermediates lead to activation of serine/threonine kinases
that phosphorylate insulin receptor substrates on serine
residues. Phosphorylated insulin receptor substrates do not
function properly, leading to impaired insulin signaling and
disruption of normal metabolic processes. Accumulation of
lipid intermediates promotes ER stress, mitochondrial dys-
function, and apoptosis (109). Dysregulation of liver and
skeletal muscle metabolism can strongly impact whole-
body glucose homeostasis and insulin sensitivity (110).
Cellular Senescence in Diabetic Complications
People with diabetes are more likely to develop age-related
morbidities, such as frailty, Alzheimer’s disease, mild cog-
nitive impairment, cardiovascular disease, osteoporosis,
visual impairment, and bladder and renal dysfunction,
indicating that T2D itself might represent a proaging state
(3). Advanced glycation end products (AGEs) are pro-
teins or lipids that become glycated when combined with
sugars. AGEs contribute to multiple microvascular and
macrovascular complications by forming of cross-links be-
tween molecules in the basement membrane of the ECM
and by engaging the receptor for advanced glycation end
products (111). In diabetes, the increased AGE formation
induces endothelial cell senescence (112). Ex vivo, endo-
thelial cells from healthy aged and T2D individuals show
chronic NF-κB activation. Blockade of NF-κB-mediated
inflammatory responses in endothelial cells prolongs the
lifespan of mice by preventing IR (113). Endothelial cell
senescence impairs systemic metabolic health (114) (Fig.
2). The presence of elevated oxidized low-density lipopro-
teins, commonly observed in diabetics, reduces the number
of circulating endothelial progenitor cells and drives their
senescence (115).
Diabetic Retinopathy
In diabetic retinopathy (DR), the microvessels in the
retina become damaged, degenerate, and regrow in an
aberrant manner. Diseased vessels show upregulation
of senescence marker expression (116). In retinas of pa-
tients with DR and in a mouse model of proliferative
DR, a high level of senescent p16INK4a-expressing cells
accumulates. Senolysis by means of genetic approaches
that clear p16Ink4a expressing cells or small molecule
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Figure 2. Diabetes and cellular senescence. Aging and obesity induce inflammation and cellular senescence in pancreatic β-cells and adipocytes.
Senescence of β-cells results in β-cell dysfunction and decreased insulin exocytosis. Senescence of adipocytes leads to ectopic lipid accumulation
and insulin resistance. Together these contribute to progression of T2D. Hyperglycemia-induced endothelial senescence plays a major role in devel-
opment of various diabetic complications such as diabetic retinopathy, diabetic nephropathy, and cardiovascular complications. Figure created with
BioRender.com.

inhibitors of the antiapoptotic protein BCL-xL, sup-
press pathological angiogenesis (116). In DR, endothelial
cells are the primary targets of glucose-induced damage.
Diabetes-induced retinal endothelial cell senescence in-
volves sequential events initiated by NADPH oxidase-2
(NOX2) activation, increased expression of its target
arginase-1 (Arg1), and ROS production (117). Increased
Arg1 expression promotes senescence through a mech-
anism involving increases in the expression of p16Ink4a,
p21Cip1, and p53 (118). Arg1 gene deletion or pharma-
cology inhibition protects against endothelial cell senes-
cence in diabetic mice (118).
Glucose-induced downregulation of SIRT1 in endothe-
lial cells promotes senescence and increases the production
of several ECM proteins and vasoactive factors in diabetes
(119). MicroRNAs (miR-34a, miR-1, miR-19b, miR-320a)
are translational suppressors of SIRT1 and also implicated
in endothelial cell senescence (120, 121). Oxidative stress
suppression of SIRT6 activity also drives endothelial cell
senescence and likely contributes to the pathogenesis of DR
(122). Endothelial cell senescence is reduced by Donepezil,
which increases SIRT1 activity (123). Senescent endothelial
cells have a secretome that attracts neutrophils and triggers
the production of neutrophil extracellular traps (NETs).
NETs ultimately clear senescent endothelial cells and re-
model unhealthy blood vessels. Genetic or pharmacological
inhibition of NETosis prevents the clearance of senescent
endothelial cells and promotes DR (124).
Cardiovascular Complications
Vascular aging contributes to the high morbidity and
mortality of cardiovascular diseases observed in patients
with diabetes. Vascular smooth muscle cells (VSMCs) are
vital components of the vascular walls and senescence of
these cells plays a key role in vascular aging. For instance,
VSMC senescence can promote vascular calcification and
atherosclerosis (125). Vascular calcification is a key com-
ponent of vasculopathy commonly seen in patients with
T2D. SnCs in proximity to blood vessel walls (eg, in peri-
vascular AT) may contribute to the cellular dysfunction
that underlies the development and progression of vas-
cular diseases such as aneurysm and atherosclerosis (126).
In VSMCs, adiponectin can reduce high-glucose-induced
senescence and may be a potential therapeutic agent for
cardiovascular complications in diabetic patients (127).
8
Diabetic Nephropathy
Diabetic nephropathy is the leading cause of chronic kidney
disease and renal failure in developed countries. In the past two
decades, the morbidity and mortality of diabetic nephropathy
have risen rapidly globally (128). The mechanisms driving dia-
betic nephropathy involve a multifactorial interaction of meta-
bolic and hemodynamic factors, including high blood glucose,
AGE, the renin–angiotensin system, and protein kinase-C–in-
duced generation of ROS, which mediates the activation of
the transcription factor NF-κB (129). Diabetic nephropathy
is strongly associated with accelerated senescence of renal
tubular cells, podocytes, mesangial cells, and endothelial cells.
Hyperglycemia can directly induce senescence in mesangial
(130) and tubular cells (131). Interestingly, high glucose can
also induce MΦ to secrete inflammatory factors, creating a
state of low-grade inflammation (129).
In both T1D and T2D, telomere attrition is associated
with renal cell senescence, proteinuria, and progression of
diabetic nephropathy (132, 133). In streptozotocin-induced
T1D mice, renal expression of p21 is increased dramatic-
ally along with an increase in SA-β-gal staining in tubular
epithelial cells. However, other cyclin-dependent kinase
inhibitors such as p16Ink4a and p27Kip1 were not altered.
In the T1D kidney, tubular senescence was induced by
hyperglycemia via a sodium-glucose transport protein 2
(SGLT2) (134). Glomerular mesangial cells, which provide
structural support for the glomerular capillary loops and
regulate the ultrafiltration surface for glomerular filtration,
are directly affected by hyperglycemia. A high extracellular
glucose concentration promotes ECM accumulation, cell
cycle arrest, cellular hypertrophy, and induces senescence
in cultured glomerular mesangial cells (135).
Conclusion
The accumulation of SnCs during aging and obesity is
involved in the pathogenesis of T1D and T2D. High glu-
cose induces senescence of a variety of cell types, which
contributes to the development of diabetic complications,
including nephropathy, retinopathy, vasculopathy, and
cardiovascular disease. Thus, SnCs play a major role in
initiating and exacerbating diabetes. Given that oral ad-
ministration of senolytic combination dasatinib and quer-
cetin (D+Q) improves insulin sensitivity and reduces the
AT inflammation in obese mice (101), 2 phase 2, random-
ized clinical trials of D+Q and the senolytic fisetin were
initiated for subjects with diabetic kidney disease at Mayo
Clinic (NCT03325322 and NCT02848131). For the D+Q
study, senolytic treatment has already been demonstrated
to reduce the senescent cell burden in AT biopsied from
obese diabetic subjects (56). Importantly, no serious drug
Endocrinology, 2021, Vol. 162, No. 10
side effects have been observed to date (56). Therefore, it
is possible that senolytics, once optimized, will be effective
in delaying the onset and reducing the severity of diabetic
complications, particularly in obese individuals.
Acknowledgements
Financial Support: This work was supported by the NIH/NIA
grants P01 R01 AG063543, R01 AG043376, U19 AG056278,
and P01 AG062413.
Conflicts of Interest: Pending patents on senolytic drugs and their
uses are held the University of Minnesota (L.J.N., P.D.R.). L.J.N. and
Downloaded from https://academic.oup.com/endo/article/162/10/bqab136/6345039 by guest on 24 March 2024
P.D.R. are co-founders of NRTK Biosciences, a startup focused on
the development of novel senolytics. L.J.N. has consulted for Merck
and Ono Pharma on senescent cells as a therapeutic target. L.J.N. and
P.D.R. are on the Scientific Advisory Board for Innate Biologics,
developing bacterial effector proteins, and P.D.R. is co-founder and
member of the Scientific Advisory Board for Genascence Corporation,
a gene therapy company focused on osteoarthritis.
Additional Information
Correspondence: Laura J. Niedernhofer, MD, PhD, Institute on
the Biology of Aging and Metabolism, Department of Biochemistry,
Molecular Biology and Biophysics, University of Minnesota Medical
School, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis,
MN 55455, USA. Email: lniedern@umn.edu.
Data Availability: Data sharing is not applicable to this art-
icle as no datasets were generated or analyzed during the current
study.
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