Science: Spermidine has antitumor effects in aging mice

Anticancer effect of spermidine in aging mice

The content of polyamine spermidine in aging mice is reduced, and polyamine spermidine supplementation has a restorative effect and prolongs life
.
Al-Habsi et al.
explored whether the loss of spermidine leads to the loss
of anti-tumor immune function in old mice.
Restoring spermidine concentration enhances antitumor response
to programmed death ligand-1 (PD-L1) monoclonal antibody therapy.
Spermidine directly affects T cell function
by increasing fatty acid oxidation.
Labeled spermidine binds to components of mitochondrial trifunctional protein complexes, thereby increasing fatty acid oxidation and ATP production
.
The authors suggest that these effects may be related to
the life-prolonging effects of spermidine.

In mammals, the ability of the immune system decreases
with age.
This is caused by a variety of factors, including a decrease and diversity of the T cell antigen repertoire due to thymic degeneration; Changes in cellular metabolism caused by inflammation; and immune cells with defective proliferation, differentiation, or viability
.
Older people often suffer from severe infections and cancers, and commonly applied treatments, including programmed cell death protein 1 (PD-1) blockade therapy, are ineffective in cancer immunotherapy
compared to younger patients.
Biogenic polyaminespermidine (SPD) decreases with age, and supplementation with SPD can improve or delay some age-related conditions, including those
of the immune system.
The mechanisms by which SPD rejuvenates the immune system include enhanced autophagy, translational activity, and mitochondrial metabolism
.
In animal models, SPD supplementation can enhance anti-tumor immunity
.
However, the relationship between SPD deficiency and aging-induced T cell immunosuppression is unclear
.

Because CD8+ T cells are key to tumor immunity, we investigated the effects of aging on the metabolic and functional properties of CD8⁺ T cells
。 We asked whether insufficient SPD was a factor
in the failure of older mice to respond to PD-1 antibody therapy.
We sought to describe the effect of SPD characterization of CD8⁺ T cells on the elderly mouse population and the molecular mechanism
of SPD action.

We found that the total and free concentrations of SPD within CD8⁺ T cells from old mice were about half
that of young mice.
Bioenergetically, compared with young CD8, mitochondrial activity of senescent CD8⁺ T cells is impaired, oxygen consumption rate, ATP production and fatty acid oxidation activity are reduced
。

We found that SPD supplementation enhanced the antitumor activity
of PD-1 blocking immunotherapy in older mice.
SPD supplementation was also effective
in young mice whose tumors did not respond to single anti-programmed death ligand 1 (PD-L1) antibody therapy.
The combination therapy of SPD and anti-PD-L1 antibody promotes in vivo proliferation of CD8⁺ T cells, cytokine production, and mitochondrial ATP production
.
In vitro, SPD can effectively enhance mitochondrial function and metabolize palmitate to tricarboxylic acid cycle components within 1h, suggesting that SPD may directly bind
to mitochondria-associated proteins.
Biochemical analysis confirmed that SPD binds to mitochondrial trifunctional protein (MTP), the core enzyme
of fatty acid β-oxidation.
β subunit consists of
β and β.
Several analyses with synthetic and purified MTP revealed that SPDs have a strong affinity [binding affinity (dissociation constant, _Kd) = 0.
1 μM] and allosteric enhance their enzymatic activity
.
In addition, we also found that spermine, another polyamine of SPD, has important cytoprotective functions, directly binds to MTP, and competitively inhibits the FAO activity of SPD, suggesting the importance of
SPD and spermine balance for FAO to evaluate senescent cells.
T cell-specific deletion of MTPα sub-blocking can block the enhancement effect of SPD on PD-1 blocking immunotherapy, indicating that MTP is required for
SPD-dependent T cell activation.

SPD supplementation enhances FAO activity, enhances mitochondrial activity and anti-cytotoxic function
of CD8+ T cells.
We provide new insights into the properties of SPD that may help develop strategies to prevent and improve age-related immunopathological outcomes and combat the non-response of PD-1 blockade therapy for cancer, regardless of age
.
SPD binds to MTP and activates FAO
in T cells.
Compared to young T cells, SPD concentrations were reduced in aging T cells, resulting in decreased
FAO activity and ATP production.
SPD supplementation activates FAO's role in elderly and young T cells, thereby improving the efficacy
of PD-1 to block tumor immunotherapy.

Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice