Who Shouldn’t Increase Their Spermidine?

That there are no reports of side effects is not surprising, since our body produces such large amounts of spermidine and it naturally occurs in the foods associated with health and a long life. But is it safe for everyone? In see.nf/spermidinedownsides I discuss who may need to be cautious about restoring their youthful spermidine levels. Spermidine may reduce cancer risk, but because the increased nutrient supply from autophagy may support tumor survival, cancer patients may not want to go overboard trying to increase their spermidine intake. The other group I would advise to be cautious are people with kidney failure.

Spermidine: bottom line

Given the safety and effectiveness of spermidine, which induces autophagy in achievable amounts, it is one of the most promising anti-aging components. DrugAge is a large online database with over 500 life-extending compounds. In the small subgroup with the fewest side effects, spermidine produces the greatest demonstrated extension of life span. A “primarily plant-based diet” has therefore been recommended to counteract the age-related decline in spermidine levels. Some foods, however, contain more spermidine than others. While there are proposals to breed high-spermidine transgenic potatoes, there are already plenty of foods that naturally contain large amounts of spermidine.

Food for Thought

Autophagy is considered the “primary system for cleansing the body” from the inside out. Some dietary components such as acrylamide can suppress autophagy, while others such as spermidine can promote the process. The chlorogenic acids in coffee can also help our cells take out the trash. What’s more, autophagy can be indirectly kick-started by increasing AMPK or suppressing mTOR.

To support this anti-aging pathway, you should daily:

Cellular senescence

50 years ago, microbiologist Leonard Hayflick demonstrated that human cells, unlike what was assumed at the time, do not keep doubling forever in a petri dish. They grow and divide only about 50 times before entering an irreversible state of arrested proliferation called cellular senescence. Senescence comes from the Latin senex, meaning “old.” We always have immortal stem cells that can generate fresh cells with a new beginning, but once these have formed, they can divide only about 50 times before they, too, are done for. That’s a good thing.

This natural “Hayflick limit” helps protect the body from cancer by preventing the proliferation of damaged cells. That’s great for getting us successfully through reproductive age and passing on our genes, but what happens when the “natural” life span of about 30 years is extended to 80 or more years by wonders like hygiene? Our bodies end up littered with senescent cells.

Zombie cells

Hayflick suspected that these no-longer-dividing cells contribute to the aging process only because they no longer participate in tissue repair and regeneration. Instead, it turned out that they actively damage the surrounding tissue, earning them the label “zombie cells.” The problem with zombies is not just that they’re no longer productive members of society. They also want to eat our brains.

When we’re younger, the immune system clears away the old cells. When cells reach their limit and are ready to retire, they’re programmed to secrete a cocktail of pro-inflammatory chemicals called the senescence-associated secretory phenotype, or SASP. Inflammation, a process often viewed as negative, is sometimes useful. Just as inflammation from a splinter summons immune cells from the circulation to the puncture site, senescent cells arrange their own burial by signing themselves up for immune clearance with inflammatory factors. But a problem arises. The older we get, the more senescent cells accumulate, while the immune system falls out of sync. So the local, temporary inflammation that, as with a splinter, is usually useful becomes a disadvantage—turning into the chronic systemic inflammation typical of aging and disease.

Even if the burden of senescent cells in aged tissue makes up only a small fraction of the total cells, their SASP secretion can have a disproportionate effect: It disrupts the architecture of local tissue and spills into the bloodstream. What is often the largest organ in the human body? Is it the liver? The skin? No. For more and more people, it’s adipose tissue—body fat. The inflammation of overweight, which worsens with age, has been linked to the buildup of SASP-producing senescent fat cells. SASP inflammation might even be responsible for some of the most feared side effects of chemotherapy. Chemo works by successfully pushing cancer cells into a senescent state, but the ensuing SASP storm can lead to bone marrow suppression and cardiotoxicity.

Given all this SASP inflammation, it’s not surprising that senescent cells are associated with a spectrum of age-related diseases such as Alzheimer’s, Parkinson’s, osteoarthritis, osteoporosis, herniated discs, spinal curvatures, loss of muscle mass, and kidney weakness. Ironically, even cancer. Although cellular senescence likely evolved as an anti-cancer mechanism, excessive inflammation later in life can actively promote tumor growth—through angiogenesis, it literally feeds the tumor with new blood vessels. But how do we know that cellular senescence is the cause rather than the consequence of disease?

Young blood

In see.nf/parabiosis I describe a series of macabre experiments showing that old animals surgically joined like Siamese twins to young animals became healthier, stronger, and smarter and lived significantly longer. To determine whether the reason was transferable factors in the blood rather than simply shared organ function, scientists moved on to giving old animals young blood. I explore these Vampire 2.0 experiments in see.nf/bloodboy.

Yes, injecting blood from young mice into old mice, for example, improves cognitive performance and suggests that young blood contains a strengthening factor, but injecting blood from old mice into young ones can worsen their condition and suggests that older blood contains a weakening factor. Or maybe the old blood just dilutes the revitalizing factor in the young mouse? By the same token, perhaps the young blood dilutes the weakening factor in the old mouse. Amazingly, it seems to be the latter, since simply diluting the blood in older animals replicates much of the regeneration found in the parabiosis and transfusion studies. And indeed, patients with mild Alzheimer’s who were randomized to blood dilution experienced about a 60 percent lower cognitive and functional decline after 14 months than the placebo group. The advantage over a blood transfusion is, as the director of the Institute of Biomedical Ethics at the University of Zurich put it: “There is something odd about the old literally sucking the young dry.”