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When Fasting Gets Tough,

the Tough Immune Cells Get Going—or Die
Roberta Buono1 and Valter D. Longo1,2,3,*
1Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue,

Los Angeles, CA 90089-0191, USA

2IFOM FIRC Institute of Molecular Oncology, Via Adamello, 16, 20139 Milan, Italy
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern

California, Los Angeles, CA, USA

*Correspondence: vlongo@usc.edu
https://doi.org/10.1016/j.cell.2019.07.052

Cycles of fasting reduce autoimmunity and activate lymphocyte-dependent killing of cancer cells,
but the mechanisms remain poorly understood. Three studies in this issue of Cell begin to reveal the
drastic and complex effects of fasting and severe calorie restriction on the levels and localization of
different immune cells and the mechanisms responsible for them.

Dietary restriction describes interventions
ranging from a chronic but minor reduc-
tion in calorie intake (calorie restriction
[CR]) to periods of water-only fasting or
fasting-mimicking diets (FMDs), which
can be intermittent and short term (‘‘inter-
mittent fasting’’ [IF] and ‘‘time-restricted
feeding’’ [TRF]), lasting less than 24 h, or
periodic and long term, lasting more
than 48 h (‘‘periodic fasting’’ [PF]) (Longo
and Panda, 2016).
These approaches have in common the
ability to downregulate evolutionarily
conserved pathways implicated in growth
and cell division, including the IGF1 and
mTOR pathways, and modulate stem
cell activation (Fontana et al., 2010). How-
ever, in the last few years, it has become
increasingly recognized that chronic die-
tary restriction, short-term IF, and long-
term PF can have very different effects
on signaling pathways, stem cells, and
immune cells. The reasons for this are
that (1) calorie restriction is chronic and

1038 Cell 178, August 22, 2019 ª 2019 Elsevier Inc.

does not include a re-feeding phase,
which appears to be important for the
cellular reprogramming and regenerative
effects caused by intermittent and peri-
odic fasting in various organs, and (2)
calorie restriction causes relatively minor
effects on the signaling pathways in-
volved in both cell death and stem cell
activation compared to the more severe
fasting interventions.
Cycles of fasting or FMDs and re-
feeding have been shown to promote
hematopoietic stem cell activation and
regeneration of immune cells (Cheng
et al., 2014), modulate gut microbiota,
ameliorate pathology in various mouse
autoimmunity models (Choi et al., 2016;
Cignarella et al., 2018; Rangan et al.,
2019), and promote the T cell-dependent
killing of cancer cells (Di Biase et al.,
2016; Pietrocola et al., 2016). However,
the mechanisms responsible for these
effects of fasting cycles on the immune
system remain poorly understood.
In this issue of Cell, three new studies
by Jordan et al., Collins et al., and by
Nagai et al. begin to shed light on these
fasting-dependent effects by investi-
gating the role of different forms of
severe dietary restriction on a range of
immune cells. They show that fasting or
severe CR causes a drastic reduction in
the number of monocytes and lympho-
cytes in the blood and in peripheral or-
gans, with both increased accumulation
of lymphocytes and reduced egress of
monocytes in the bone marrow. Nagai
et al. focused on the gut immune
response, where they showed that multi-
ple and frequent cycles of water-only
fasting attenuated the normal immune
response of mice to oral immunization.
In this study, the loss of a large portion
of germinal center and IgA+ B cells in
the Payer’s patches (PPs) is caused by
apoptosis (Nagai et al., 2019). Fasting
downregulates the CXCL13-CXCR5
pathway in B naive cells of the PPs and
CCL2-CCR2 pathway in monocytes of
the bone marrow (BM), whereas CR in-
creases the CXCL12-CXCR4 pathway in
memory T cells; these signaling path-
ways are restored by re-feeding, leading
to major changes in cellular composition.
Notably, these results are in agreement
with previous findings that water-only
fasting cycles can promote limited
changes in the gut microbiota and result
in increased leakiness (Rangan et al.,
2019). Similarly, Jordan et al. found that
a 48 h water-only fast reduced monocyte
mobilization after Listeria infection or
wound healing (Jordan et al., 2019). By
contrast, Collins et al. showed enhanced
protection against infections and tumors
when only a 50% calorie restriction was
applied instead of water-only fasting
(Collins et al., 2019). These studies raise
the possibility that a complete lack of
nutrients, but not the partial fasting
conditions, may result in some immune
impairments.
The differing results of Jordan et al.
and Collins et al. together demonstrate
the potent but complex effects of fasting
and FMDs on the levels of monocytes
and of both B and T cells. For instance,
Jordan et al. discovered that the liver
AMPK-PPRa pathway controls the level
of peripheral monocytes and that
the liver secretome contains different
circulating factors that modulate the level
of chemokine CCL2 and control the
monocyte egress from the BM. Collins
et al. instead propose that the glucocor-
ticoids levels together with the higher
number of adipocytes and erythropoietic
cells mediate the accumulation of
memory T cells in the BM and that inhibi-
tion of the mTOR pathway promotes
lymphocyte survival in response to se-
vere calorie restriction. Some of these
differences may be explained by the fast-
ing duration and severity. In response to
food deprivation, the mice may begin to
reduce investment in immune cells by
reducing their number at least in circula-
tion and in secondary lymphoid organs.
Notably, Jordan et al. also show a reduc-
tion of circulating monocytes in patients
undergoing a relatively short 19 h fast in
agreement with the reduction in total
lymphocyte count in over 70% of multi-
ple sclerosis patients undergoing a
7-day long FMD (Choi et al., 2016). How-
ever, the mouse studies indicate that at
least part of the major decrease in circu-
lating immune cells appears to be due to
redistribution of these cells to the bone
marrow. Thus, the three new studies
demonstrate the ability of different forms
of fasting, as well as different lengths of
fasting, to cause potent but distinct and
at times opposite effects on the levels
and function of various immune cell
types, thus underlining the need to
replace terms like fasting, or intermittent
fasting, with those that describe the
type and length of the fasting method
such as a 24 h alternate-day fasting
(24 H ADF), a 12 h time-restricted
feeding (12 H TRF), or a 5-day fasting-
mimicking diet (5-day FMD). Without
these more precise definitions, it will
be difficult to generate sufficient data
to enhance our understanding of the
biology of fasting responses and begin
to translate this knowledge into random-
ized clinical trials.
Undoubtedly, the preclinical and clin-
ical data presented here and in earlier
studies are beginning to indicate that
certain forms of fasting and specific
compositions of these fasting-like diets
can promote potent and coordinated
immunomodulatory effects with the
potential to be effective alone or in
combination with drugs or biologicals
against autoimmune diseases, cancer,
neurodegeneration, and other diseases
involving the microbiota and immune
system.
DECLARATION OF INTERESTS
Valter Longo has equity interest in L-Nutra, a
company that produces medical food.
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