Zinc

Supports immunity

The clearest proof that zinc runs the immune system came from the people who first showed it was essential. In the 1960s Ananda Prasad described young men in Iran and Egypt with severe dietary zinc deficiency: they were stunted and sexually immature, and most died of infections by about age 25. Later, Prasad's group made healthy volunteers mildly zinc-deficient on a controlled diet. Their T helper cells were hit first.¹

Several separate jobs depend on zinc:

• Making T cells. The thymus trains T cells using a hormone called thymulin, which only works with zinc bound to it. Low zinc means less active thymulin, a shrinking thymus and fewer new T cells.
• The "go" signal. When a T helper cell spots an invader it makes interleukin-2 (IL-2), which tells T cells to multiply. In zinc-deficient cells, the switch that turns on the IL-2 gene (NF-κB) binds DNA poorly, so less IL-2 is made and fewer T cells answer the call.¹
• The "stop" signal. Zinc also switches on a brake protein called A20, which lowers inflammatory cytokines (TNF-α, IL-1β, IL-8) once the job is done. In supplementation studies with young and elderly adults, zinc lowered markers of oxidative stress and inflammatory cytokines.¹ So zinc does not just turn immunity up. It keeps the response strong when needed and turns it off afterward.
• Front-line cells. Neutrophils and natural killer cells both work less well when zinc is low, and the thymus and lymph tissue shrink.

Human trial evidence. Zinc lozenges shorten the common cold. A meta-analysis of seven randomised trials (575 people) found colds were 33% shorter with lozenges supplying 80–92 mg/day, and doses above 100 mg/day did no better.² The effect probably comes from zinc ions released in the throat, where cold viruses grow. That dose is above the 40 mg upper limit, so this is a short course of a few days at the first sign of a cold, not a daily habit.

More isn't better. Taking more than about 100 mg/day for weeks suppresses immunity again, mostly by causing copper deficiency, which lowers neutrophil counts. See zinc and copper.

Heals wounds and skin

About 5% of the body's zinc is in the skin, and the outer layer (epidermis) holds several times more per gram than the deeper layer (dermis). Skin has a high zinc need because it is always replacing itself, and every step of repair uses zinc-dependent enzymes:³

• Clot and clean-up. Zinc released from platelets and damaged cells helps start the inflammatory phase, and immune cells need zinc to clear bacteria and debris from the wound (see immunity).
• Rebuilding. Fibroblasts and keratinocytes have to multiply fast to fill the gap. Copying DNA and making new protein relies on zinc-dependent polymerases and on zinc finger transcription factors (see gene control). Without enough zinc, cell division and collagen production slow down.
• Moving in and remodelling. To move across a wound, skin cells have to cut through the surrounding scaffolding. The enzymes that do this, the matrix metalloproteinases (MMPs), carry a zinc ion in their active site. They also later remodel the scar.
• Membrane repair and antioxidant protection. Zinc helps damaged cell membranes reseal and is part of the antioxidant enzyme SOD1 (see cancer risk), which protects new tissue from oxidative damage.

Human evidence. The most dramatic case is the genetic disease acrodermatitis enteropathica. A faulty zinc transporter (ZIP4) in the gut means zinc can't be absorbed. Babies with it develop raw, crusted rashes around the mouth, hands and genitals, hair loss, diarrhoea and repeated infections, and the disease used to be fatal. Oral zinc cures it completely, which shows zinc is required for healthy skin. In ordinary dietary deficiency (common in the elderly, people with alcoholism, malabsorption, burns or chronic wounds) healing is slower, and replacing zinc brings it back to normal.³

Fixes a shortage, doesn't speed up normal healing. In people whose zinc is already adequate, extra oral zinc does not make wounds heal faster. The benefit comes from correcting a deficiency, so it's worth checking for one when a wound won't close.

Controls genes

About 10% of all human proteins (~2,800) bind zinc, and most of them help control which genes are turned on. Zinc fingers are the largest group.⁴ They were found in 1985 in a frog protein called TFIIIA. That protein had a short pattern repeated nine times, and each repeat held one zinc atom.⁵

How a zinc finger works. Each finger is a stretch of about 30 amino acids. Alone, that chain is too short to fold into a stable shape. Zinc holds it together: two cysteines on one part of the chain and two histidines on another all grip the same zinc ion. That pulls the chain into a fixed shape, a small hairpin packed against a short helix. The helix then fits into the major groove of DNA, where its side chains can "read" about three base pairs. A transcription factor strings several fingers together, so it can recognise a longer DNA "address" (9, 12, 18 bases) and turn on just the genes near it.⁵

Why it matters for the rest of the body. There are more than 700 genes for this kind of zinc finger protein, making it the biggest family of gene switches in the human genome. A second type of zinc finger, held by four cysteines, forms the DNA-binding part of the nuclear hormone receptors. These are the receptors for vitamin D, thyroid hormone, oestrogen, testosterone and cortisol. Each receptor uses two of these fingers to find its target genes. So a hormone signal that reaches the cell still needs zinc to hold the receptor in shape before any gene can change. Zinc is also bound in the DNA-binding domain of the tumour suppressor p53 and in several DNA-repair enzymes (see cancer risk). The same zinc-dependent switches also drive the fast cell division needed in wound repair and immune responses.

What's proven and what isn't. It's settled structural biology that zinc fingers need zinc to fold. They bind it very tightly, though, and cells guard their zinc supply, so a mild dietary shortfall won't strip zinc from every finger at once. Deficiency clearly changes gene expression in people and animals, and growth stalls in severe deficiency. But it hasn't been measured how many fingers lose their zinc in living tissue at a given intake.

Cancer risk and zinc status

Zinc deficiency creates an inflamed environment where cancer can take hold, while enough zinc appears to block tumour formation outright. Taccioli et al. (2012) fed rats a zinc-deficient diet for 21 weeks alongside the oesophageal carcinogen NMBA. Zinc-deficient animals developed oesophageal squamous cell carcinoma in 67% of cases. Zinc-sufficient animals exposed to the same carcinogen developed cancer in 0%. Restoring zinc reversed the pre-cancerous inflammatory gene pattern at both the dysplastic and the tumour stages. Time-course analysis showed the inflammation was caused by the zinc deficiency, not by the carcinogen.⁶

The mechanism works at two levels:

• SOD activity. Zinc is part of the antioxidant enzyme Cu/Zn-SOD (SOD1) in the cell's cytosol and supports Mn-SOD (SOD2) inside mitochondria. These are the main antioxidant enzymes at both sites. Deficiency lowers their activity and raises superoxide at the electron transport chain. That drives the kind of mitochondrial oxidative damage (cardiolipin peroxidation, ETC impairment) described in the cancer-as-metabolic-disease literature.
• DNA repair and tumour suppression. The DNA-binding domain of p53 holds a zinc ion it needs to keep its shape, and several DNA-repair enzymes depend on zinc fingers (see gene control). Zinc deficiency weakens this DNA-monitoring machinery. The gene pattern caused by deficiency, more than 100 inflammatory genes switched on, including S100a8, S100a9, CXC/CC chemokines, cytokines and Cxcr-2, was already present at the dysplastic stage, before any cancer was visible.

Animal model only. This is rat oesophageal squamous cell carcinoma caused by a chemical carcinogen. No randomised trial has tested whether getting enough zinc from food lowers cancer rates in humans. The finding fits the known mechanisms and the effect is striking, but it can't be applied directly to humans. See also Cancer & Metabolic Disease for the broader metabolic context.

Intake

RDA 8 mg/day (women), 11 mg/day (men); upper limit 40 mg/day (adults). The body has no real zinc store, so it needs a steady daily supply. Phytate in whole grains and legumes binds zinc in the gut and blocks absorption unless the food is soaked, sprouted or fermented first. Zinc from animal foods is absorbed much better.

Top foods

• Oysters: about 32 mg in 3 oz, roughly three days' worth. See Freeze-Dried Oyster.
• Beef: about 7 mg in 3 oz of chuck roast.
• Crab and other shellfish: about 6.5 mg in 3 oz of Alaska king crab.
• Pumpkin seeds: about 2.2 mg in 1 oz (about 3 tbsp).

Deficiency effects

Weak immunity and frequent infections, slow wound healing, hair loss, and changes in taste or smell. Severe deficiency causes stunted growth, delayed puberty and skin lesions, as in Prasad's original patients and in acrodermatitis enteropathica.¹ People most at risk: those on high-phytate plant diets, the elderly, heavy drinkers, and people with gut malabsorption or chronic wounds.

Zinc and copper

High-dose zinc taken on its own for a long time can cause copper deficiency. Zinc makes gut cells produce metallothionein, a protein that binds copper more tightly than zinc. The copper gets trapped in those cells and is lost when they shed. The result can be anaemia, low neutrophils and, over time, nerve damage. Food sources like oysters and beef also supply copper, which is one reason to get zinc from food. See Copper.